16-15724985-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_002474.3(MYH11):c.3866T>C(p.Val1289Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0564 in 1,613,508 control chromosomes in the GnomAD database, including 3,024 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1289L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.040 (164 hom., cov: 32)
  • Exomes 𝑓: 0.058 (2860 hom.)
• Consequence: MYH11 NM_002474.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 7.34

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MYH11
• BP4: Computational evidence support a benign effect (MetaRNN=0.0034478605).
• BP6: Variant 16-15724985-A-G is Benign according to our data. Variant chr16-15724985-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 138337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15724985-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH11	NM_002474.3	c.3866T>C	p.Val1289Ala	missense_variant	29/41	ENST00000300036.6
MYH11	NM_001040113.2	c.3887T>C	p.Val1296Ala	missense_variant	30/43	ENST00000452625.7
NDE1	NM_017668.3	c.*734A>G		3_prime_UTR_variant	9/9	ENST00000396354.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH11	ENST00000300036.6	c.3866T>C	p.Val1289Ala	missense_variant	29/41	1	NM_002474.3	P3
MYH11	ENST00000452625.7	c.3887T>C	p.Val1296Ala	missense_variant	30/43	1	NM_001040113.2
NDE1	ENST00000396354.6	c.*734A>G		3_prime_UTR_variant	9/9	1	NM_017668.3	P1

Frequencies

GnomAD3 genomes AF: 0.0402 AC: 6113 AN: 152054 Hom.: 164 Cov.: 32

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0347

Gnomad ASJ AF: 0.0571

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.0138

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0665

Gnomad OTH AF: 0.0403

GnomAD3 exomes AF: 0.0396 AC: 9944 AN: 251062 Hom.: 294 AF XY: 0.0411 AC XY: 5576 AN XY: 135726

Gnomad AFR exome AF: 0.00986

Gnomad AMR exome AF: 0.0229

Gnomad ASJ exome AF: 0.0639

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0261

Gnomad FIN exome AF: 0.0157

Gnomad NFE exome AF: 0.0611

Gnomad OTH exome AF: 0.0449

GnomAD4 exome AF: 0.0581 AC: 84925 AN: 1461336 Hom.: 2860 Cov.: 34 AF XY: 0.0575 AC XY: 41802 AN XY: 727002

Gnomad4 AFR exome AF: 0.00923

Gnomad4 AMR exome AF: 0.0245

Gnomad4 ASJ exome AF: 0.0626

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0277

Gnomad4 FIN exome AF: 0.0183

Gnomad4 NFE exome AF: 0.0672

Gnomad4 OTH exome AF: 0.0577

GnomAD4 genome AF: 0.0402 AC: 6112 AN: 152172 Hom.: 164 Cov.: 32 AF XY: 0.0364 AC XY: 2710 AN XY: 74398

Gnomad4 AFR AF: 0.0114

Gnomad4 AMR AF: 0.0347

Gnomad4 ASJ AF: 0.0571

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0235

Gnomad4 FIN AF: 0.0138

Gnomad4 NFE AF: 0.0665

Gnomad4 OTH AF: 0.0399

Alfa AF: 0.0583 Hom.: 460

Bravo AF: 0.0407

TwinsUK AF: 0.0647 AC: 240

ALSPAC AF: 0.0605 AC: 233

ESP6500AA AF: 0.0137 AC: 60

ESP6500EA AF: 0.0651 AC: 560

ExAC AF: 0.0388 AC: 4711

Asia WGS AF: 0.00924 AC: 33 AN: 3478

EpiCase AF: 0.0638

EpiControl AF: 0.0587

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Val1296Ala in exon 30 of MYH11: This variant is not expected to have clinical si gnificance because it has been identified in 6.5% (560/8600) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs16967510). -

Aortic aneurysm, familial thoracic 4 Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Feb 04, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 19, 2015	General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Lissencephaly 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2014

This alteration is classified as benign based on a combination of the following: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	21
Dann	Uncertain	0.98
Eigen	Benign	-0.13
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;D;D
MetaRNN	Benign	0.0034	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.3	N;N;.;N
REVEL	Benign	0.20
Sift	Benign	0.16	T;T;.;T
Sift4G	Benign	0.56	T;T;T;T
Polyphen		0.069	.;.;.;B
Vest4		0.30
MPC		0.28
ClinPred		0.028	T
GERP RS		5.2
Varity_R		0.094
gMVP		0.22

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

LitVar

Other links and lift over

dbSNP: rs16967510; hg19: chr16-15818842; COSMIC: COSV55553257; COSMIC: COSV55553257;