NM_002474.3:c.3651+5delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_002474.3(MYH11):​c.3651+5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,614,244 control chromosomes in the GnomAD database, including 56 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 27 hom., cov: 32)
Exomes 𝑓: 0.0011 ( 29 hom. )

Consequence

MYH11
NM_002474.3 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.223

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 -16 ACMG points.

BP6
Variant 16-15732558-CA-C is Benign according to our data. Variant chr16-15732558-CA-C is described in ClinVar as [Benign]. Clinvar id is 264115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0107 (1626/152356) while in subpopulation AFR AF = 0.037 (1539/41576). AF 95% confidence interval is 0.0355. There are 27 homozygotes in GnomAd4. There are 791 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 27 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYH11NM_002474.3 linkc.3651+5delT splice_region_variant, intron_variant Intron 27 of 40 ENST00000300036.6 NP_002465.1 P35749-1A0A024QZJ4
MYH11NM_001040113.2 linkc.3672+5delT splice_region_variant, intron_variant Intron 28 of 42 ENST00000452625.7 NP_001035202.1 P35749-3
MYH11NM_001040114.2 linkc.3672+5delT splice_region_variant, intron_variant Intron 28 of 41 NP_001035203.1 P35749-2
MYH11NM_022844.3 linkc.3651+5delT splice_region_variant, intron_variant Intron 27 of 41 NP_074035.1 P35749-4A0A024QZJ6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH11ENST00000300036.6 linkc.3651+5delT splice_region_variant, intron_variant Intron 27 of 40 1 NM_002474.3 ENSP00000300036.5 P35749-1
MYH11ENST00000452625.7 linkc.3672+5delT splice_region_variant, intron_variant Intron 28 of 42 1 NM_001040113.2 ENSP00000407821.2 P35749-3

Frequencies

GnomAD3 genomes
AF:
0.0106
AC:
1619
AN:
152238
Hom.:
26
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0370
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00406
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0158
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.00574
GnomAD2 exomes
AF:
0.000638
AC:
160
AN:
250868
AF XY:
0.000354
show subpopulations
Gnomad AFR exome
AF:
0.00945
Gnomad AMR exome
AF:
0.000260
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00108
AC:
1575
AN:
1461888
Hom.:
29
Cov.:
31
AF XY:
0.000961
AC XY:
699
AN XY:
727246
show subpopulations
African (AFR)
AF:
0.0387
AC:
1296
AN:
33480
American (AMR)
AF:
0.00152
AC:
68
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.000128
AC:
11
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.00260
AC:
15
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000279
AC:
31
AN:
1112010
Other (OTH)
AF:
0.00255
AC:
154
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.436
Heterozygous variant carriers
0
87
174
260
347
434
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
42
84
126
168
210
<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:
0.0107
AC:
1626
AN:
152356
Hom.:
27
Cov.:
32
AF XY:
0.0106
AC XY:
791
AN XY:
74510
show subpopulations
African (AFR)
AF:
0.0370
AC:
1539
AN:
41576
American (AMR)
AF:
0.00405
AC:
62
AN:
15300
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5192
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
0.0170
AC:
5
AN:
294
European-Non Finnish (NFE)
AF:
0.000118
AC:
8
AN:
68042
Other (OTH)
AF:
0.00568
AC:
12
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
85
170
254
339
424
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
20
40
60
80
100
<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:
0.0000525
Hom.:
0
Asia WGS
AF:
0.00346
AC:
12
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:2
Jul 07, 2015
Ambry Genetics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jul 15, 2018
Color Diagnostics, LLC DBA Color Health
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Aortic aneurysm, familial thoracic 4 Benign:1
Nov 04, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

MYH11-related disorder Benign:1
Feb 19, 2019
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1
Mar 03, 2015
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
0.22
Mutation Taster
=59/41
polymorphism (auto)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs201404398; hg19: chr16-15826415; API