16-15708829-TGGG-TGGGG

Variant names:

• chr16-15708829-T-TG
• rs747392139
• NM_001040113.2:c.5819dupC

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PVS1_Moderate BP6 BS1

The NM_001040113.2(MYH11):​c.5819dupC​(p.Gln1941ThrfsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000313 in 1,603,076 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: MYH11 NM_001040113.2 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 1.54
• Publications: 12 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00325 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• BP6: Variant 16-15708829-T-TG is Benign according to our data. Variant chr16-15708829-T-TG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 238263.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000198 (30/151762) while in subpopulation EAS AF = 0.000386 (2/5176). AF 95% confidence interval is 0.000204. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040113.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	NM_001040113.2	MANE Plus Clinical	c.5819dupC	p.Gln1941ThrfsTer20	frameshift	Exon 42 of 43	NP_001035202.1
	MYH11	NM_002474.3	MANE Select	c.5787-4707dupC		intron	N/A	NP_002465.1
	NDE1	NM_017668.3	MANE Select	c.947+11977dupG		intron	N/A	NP_060138.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH11	ENST00000452625.7	TSL:1 MANE Plus Clinical	c.5819dupC	p.Gln1941ThrfsTer20	frameshift	Exon 42 of 43	ENSP00000407821.2
	MYH11	ENST00000576790.7	TSL:1	c.5798dupC	p.Gln1934ThrfsTer12	frameshift	Exon 41 of 42	ENSP00000458731.1
	MYH11	ENST00000300036.6	TSL:1 MANE Select	c.5787-4707dupC		intron	N/A	ENSP00000300036.5

Frequencies

GnomAD3 genomes AF: 0.000198 AC: 30 AN: 151644 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000721 AC: 169 AN: 234464 AF XY: 0.000474

Gnomad AFR exome AF: 0.000962

Gnomad AMR exome AF: 0.000215

Gnomad ASJ exome AF: 0.00104

Gnomad EAS exome AF: 0.000572

Gnomad FIN exome AF: 0.0000483

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.00121

GnomAD4 exome AF: 0.000325 AC: 471 AN: 1451314 Hom.: 0 Cov.: 32 AF XY: 0.000328 AC XY: 237 AN XY: 721560

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000330 AC: 11 AN: 33330

American (AMR) AF: 0.000182 AC: 8 AN: 43928

Ashkenazi Jewish (ASJ) AF: 0.0000772 AC: 2 AN: 25908

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39596

South Asian (SAS) AF: 0.000165 AC: 14 AN: 84708

European-Finnish (FIN) AF: 0.00255 AC: 134 AN: 52582

Middle Eastern (MID) AF: 0.000696 AC: 4 AN: 5750

European-Non Finnish (NFE) AF: 0.000252 AC: 279 AN: 1105488

Other (OTH) AF: 0.000250 AC: 15 AN: 60024

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000198 AC: 30 AN: 151762 Hom.: 0 Cov.: 33 AF XY: 0.000189 AC XY: 14 AN XY: 74190

African (AFR) AF: 0.000338 AC: 14 AN: 41382

American (AMR) AF: 0.000198 AC: 3 AN: 15182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67902

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.000391 Hom.: 0

Bravo AF: 0.000219

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Feb 21, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1 Benign:1

Apr 04, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 16, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

Apr 01, 2019

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYH11 c.5819dupC (p.Gln1941ThrfsX20) changes the termination codon and is predicted to lead to an extended protein with additional amino acids added to the normal C-terminus. MYH11 c.5819dupC (p.Gln1941ThrfsX20) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 0.0038 in 81378 control chromosomes, predominantly at a frequency of 0.0048 within the Non-Finnish European subpopulation in the ExAC database. The observed variant frequency within Non-Finnish European control individuals in the ExAC database is approximately 3840 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 Non-Finnish European origin. To our knowledge, no occurrence of c.5819dupC in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

Nov 06, 2017

GeneDx

Significance: Likely 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.

Aortic aneurysm, familial thoracic 4 Benign:1

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYH11-related disorder Benign:1

Sep 17, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=66/134	disease causing

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: rs747392139; hg19: chr16-15802686; COSMIC: COSV55546050; COSMIC: COSV55546050;