16-15718451-C-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_002474.3(MYH11):​c.5172-13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,549,502 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

MYH11
NM_002474.3 intron

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 0.683

Publications

1 publications found
Variant links:
Genes affected
MYH11 (HGNC:7569): (myosin heavy chain 11) The protein encoded by this gene is a smooth muscle myosin belonging to the myosin heavy chain family. The gene product is a subunit of a hexameric protein that consists of two heavy chain subunits and two pairs of non-identical light chain subunits. It functions as a major contractile protein, converting chemical energy into mechanical energy through the hydrolysis of ATP. A chromosomal rearrangement involving this gene is associated with acute myeloid leukemia of the M4Eo subtype. Mutations in this gene are associated with visceral myopathy, megacystis-microcolon-intestinal hypoperistalsis syndrome 2, and familial thoracic aortic aneurysm 4. [provided by RefSeq, May 2022]
NDE1 (HGNC:17619): (nudE neurodevelopment protein 1) This gene encodes a member of the nuclear distribution E (NudE) family of proteins. The encoded protein is localized at the centrosome and interacts with other centrosome components as part of a multiprotein complex that regulates dynein function. This protein plays an essential role in microtubule organization, mitosis and neuronal migration. Mutations in this gene cause lissencephaly 4, a disorder characterized by lissencephaly, severe brain atrophy, microcephaly, and severe cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]
NDE1 Gene-Disease associations (from GenCC):
  • lissencephaly 4
    Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
  • hydranencephaly
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • microlissencephaly
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • NDE1-related microhydranencephaly
    Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
Variant 16-15718451-C-T is Benign according to our data. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036. Variant chr16-15718451-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 201036.
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000177 (27/152286) while in subpopulation AFR AF = 0.00012 (5/41576). AF 95% confidence interval is 0.0000473. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYH11NM_002474.3 linkc.5172-13G>A intron_variant Intron 36 of 40 ENST00000300036.6 NP_002465.1 P35749-1A0A024QZJ4
MYH11NM_001040113.2 linkc.5193-13G>A intron_variant Intron 37 of 42 ENST00000452625.7 NP_001035202.1 P35749-3
NDE1NM_017668.3 linkc.948-5740C>T intron_variant Intron 8 of 8 ENST00000396354.6 NP_060138.1 Q9NXR1-2X5DR54

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH11ENST00000300036.6 linkc.5172-13G>A intron_variant Intron 36 of 40 1 NM_002474.3 ENSP00000300036.5 P35749-1
MYH11ENST00000452625.7 linkc.5193-13G>A intron_variant Intron 37 of 42 1 NM_001040113.2 ENSP00000407821.2 P35749-3
NDE1ENST00000396354.6 linkc.948-5740C>T intron_variant Intron 8 of 8 1 NM_017668.3 ENSP00000379642.1 Q9NXR1-2

Frequencies

GnomAD3 genomes
AF:
0.000177
AC:
27
AN:
152168
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00519
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.000478
GnomAD2 exomes
AF:
0.000332
AC:
53
AN:
159540
AF XY:
0.000349
show subpopulations
Gnomad AFR exome
AF:
0.000106
Gnomad AMR exome
AF:
0.0000388
Gnomad ASJ exome
AF:
0.00491
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000458
Gnomad OTH exome
AF:
0.00108
GnomAD4 exome
AF:
0.000129
AC:
180
AN:
1397216
Hom.:
1
Cov.:
31
AF XY:
0.000136
AC XY:
94
AN XY:
691144
show subpopulations
African (AFR)
AF:
0.0000312
AC:
1
AN:
32096
American (AMR)
AF:
0.0000270
AC:
1
AN:
37060
Ashkenazi Jewish (ASJ)
AF:
0.00552
AC:
140
AN:
25362
East Asian (EAS)
AF:
0.0000273
AC:
1
AN:
36590
South Asian (SAS)
AF:
0.0000122
AC:
1
AN:
81678
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
38710
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4754
European-Non Finnish (NFE)
AF:
0.0000249
AC:
27
AN:
1082864
Other (OTH)
AF:
0.000155
AC:
9
AN:
58102
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.489
Heterozygous variant carriers
0
11
23
34
46
57
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000177
AC:
27
AN:
152286
Hom.:
0
Cov.:
32
AF XY:
0.000161
AC XY:
12
AN XY:
74460
show subpopulations
African (AFR)
AF:
0.000120
AC:
5
AN:
41576
American (AMR)
AF:
0.00
AC:
0
AN:
15296
Ashkenazi Jewish (ASJ)
AF:
0.00519
AC:
18
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5166
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000441
AC:
3
AN:
68016
Other (OTH)
AF:
0.000473
AC:
1
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.490
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000781
Hom.:
0
Bravo
AF:
0.000151

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Aortic aneurysm, familial thoracic 4 Uncertain:1Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jan 19, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:2
Nov 11, 2014
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jul 14, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

c.5193-13G>A in intron 37 of MYH11: This variant is not expected to have clinica l significance because it is not located within the splice consensus sequence. I t has been identified in 0.1% (11/11814) of European chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs373378619). -

Familial thoracic aortic aneurysm and aortic dissection Benign:2
Feb 05, 2024
All of Us Research Program, National Institutes of Health
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 16, 2018
Color Diagnostics, LLC DBA Color Health
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Lissencephaly, Recessive Uncertain:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.83
CADD
Benign
7.3
DANN
Benign
0.76
PhyloP100
0.68
Mutation Taster
=100/0
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs373378619; hg19: chr16-15812308; API