chr16-15724635-C-T

Variant names:

• chr16-15724635-C-T
• rs193005461
• NM_017668.3:c.*384C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017668.3(NDE1):​c.*384C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,613,748 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (13 hom.)
• Consequence: NDE1 NM_017668.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.751
• Publications: 2 publications found

Genes affected

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]

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]

MYH11 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• aortic aneurysm, familial thoracic 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• megacystis-microcolon-intestinal hypoperistalsis syndrome 2

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• megacystis-microcolon-intestinal hypoperistalsis syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• visceral myopathy 2

  Inheritance: AR, AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-15724635-C-T is Benign according to our data. Variant chr16-15724635-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 138340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15724635-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 138340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15724635-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 138340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15724635-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 138340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15724635-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 138340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15724635-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 138340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15724635-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 138340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15724635-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 138340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15724635-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 138340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15724635-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 138340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15724635-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 138340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15724635-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 138340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15724635-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 138340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15724635-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 138340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15724635-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 138340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15724635-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 138340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15724635-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 138340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15724635-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 138340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15724635-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 138340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15724635-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 138340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15724635-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 138340.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 = 0.00775 (1180/152250) while in subpopulation AFR AF = 0.0276 (1145/41548). AF 95% confidence interval is 0.0262. There are 16 homozygotes in GnomAd4. There are 572 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDE1	NM_017668.3	c.*384C>T		3_prime_UTR_variant	Exon 9 of 9	ENST00000396354.6	NP_060138.1
MYH11	NM_002474.3	c.4116+12G>A		intron_variant	Intron 30 of 40	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.4137+12G>A		intron_variant	Intron 31 of 42	ENST00000452625.7	NP_001035202.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDE1	ENST00000396354.6	c.*384C>T		3_prime_UTR_variant	Exon 9 of 9	1	NM_017668.3	ENSP00000379642.1
MYH11	ENST00000300036.6	c.4116+12G>A		intron_variant	Intron 30 of 40	1	NM_002474.3	ENSP00000300036.5
MYH11	ENST00000452625.7	c.4137+12G>A		intron_variant	Intron 31 of 42	1	NM_001040113.2	ENSP00000407821.2

Frequencies

GnomAD3 genomes AF: 0.00773 AC: 1176 AN: 152132 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00203 AC: 509 AN: 251178 AF XY: 0.00152

Gnomad AFR exome AF: 0.0285

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000740 AC: 1082 AN: 1461498 Hom.: 13 Cov.: 34 AF XY: 0.000637 AC XY: 463 AN XY: 727030

African (AFR) AF: 0.0270 AC: 903 AN: 33474

American (AMR) AF: 0.000894 AC: 40 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00146 AC: 8 AN: 5470

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1112010

Other (OTH) AF: 0.00156 AC: 94 AN: 60342

GnomAD4 genome AF: 0.00775 AC: 1180 AN: 152250 Hom.: 16 Cov.: 32 AF XY: 0.00768 AC XY: 572 AN XY: 74452

African (AFR) AF: 0.0276 AC: 1145 AN: 41548

American (AMR) AF: 0.00150 AC: 23 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68010

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00438 Hom.: 1

Bravo AF: 0.00864

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Dec 03, 2013

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 19, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYH11 c.4137+12G>A alters a nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.002 in 251178 control chromosomes, predominantly at a frequency of 0.028 within the African or African-American subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 22400 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.4137+12G>A in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Aortic aneurysm, familial thoracic 4 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Apr 21, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Lissencephaly 4 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Lissencephaly, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.6
DANN	Benign	0.57
PhyloP100		-0.75
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs193005461; hg19: chr16-15818492;