NM_002471.4:c.3010G>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002471.4(MYH6):​c.3010G>T​(p.Ala1004Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,614,160 control chromosomes in the GnomAD database, including 2 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 0.0011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

MYH6
NM_002471.4 missense

Scores

9
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4B:16

Conservation

PhyloP100: 2.47
Variant links:
Genes affected
MYH6 (HGNC:7576): (myosin heavy chain 6) Cardiac muscle myosin is a hexamer consisting of two heavy chain subunits, two light chain subunits, and two regulatory subunits. This gene encodes the alpha heavy chain subunit of cardiac myosin. The gene is located approximately 4kb downstream of the gene encoding the beta heavy chain subunit of cardiac myosin. Mutations in this gene cause familial hypertrophic cardiomyopathy and atrial septal defect 3. [provided by RefSeq, Feb 2017]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.02393347).
BP6
Variant 14-23393437-C-A is Benign according to our data. Variant chr14-23393437-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14151.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Pathogenic=1, Likely_benign=11, Likely_pathogenic=1}. Variant chr14-23393437-C-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00109 (166/152268) while in subpopulation AMR AF= 0.00314 (48/15294). AF 95% confidence interval is 0.00243. There are 0 homozygotes in gnomad4. There are 87 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 166 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYH6NM_002471.4 linkc.3010G>T p.Ala1004Ser missense_variant Exon 23 of 39 ENST00000405093.9 NP_002462.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH6ENST00000405093.9 linkc.3010G>T p.Ala1004Ser missense_variant Exon 23 of 39 5 NM_002471.4 ENSP00000386041.3 P13533

Frequencies

GnomAD3 genomes
AF:
0.00109
AC:
166
AN:
152150
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00314
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000754
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00141
Gnomad OTH
AF:
0.00192
GnomAD3 exomes
AF:
0.000926
AC:
233
AN:
251486
Hom.:
0
AF XY:
0.000934
AC XY:
127
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.00211
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000508
Gnomad NFE exome
AF:
0.00120
Gnomad OTH exome
AF:
0.00147
GnomAD4 exome
AF:
0.00110
AC:
1603
AN:
1461892
Hom.:
2
Cov.:
33
AF XY:
0.00105
AC XY:
763
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.000269
Gnomad4 AMR exome
AF:
0.00195
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.000618
Gnomad4 NFE exome
AF:
0.00125
Gnomad4 OTH exome
AF:
0.00127
GnomAD4 genome
AF:
0.00109
AC:
166
AN:
152268
Hom.:
0
Cov.:
32
AF XY:
0.00117
AC XY:
87
AN XY:
74452
show subpopulations
Gnomad4 AFR
AF:
0.000241
Gnomad4 AMR
AF:
0.00314
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000754
Gnomad4 NFE
AF:
0.00141
Gnomad4 OTH
AF:
0.00190
Alfa
AF:
0.00105
Hom.:
0
Bravo
AF:
0.00123
TwinsUK
AF:
0.00135
AC:
5
ALSPAC
AF:
0.00208
AC:
8
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00128
AC:
11
ExAC
AF:
0.000980
AC:
119
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000872
EpiControl
AF:
0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:4Benign:16
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:7
May 15, 2020
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 11, 2013
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

MYH6: BS1 -

not specified Benign:4
Jul 16, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

p.Ala1004Ser in exon 23 of MYH6: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (31/11578) of Latino chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs143978652). -

Sep 08, 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. -

-
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 29, 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: MYH6 c.3010G>T (p.Ala1004Ser) results in a conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00093 in 251486 control chromosomes, predominantly at a frequency of 0.0021 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 84 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.3010G>T has been reported in the literature in sequencing studies among individuals affected with Cardiomyopathy (Carniel_2005, Brion_2009, Brion_2012, Hershberger_2010, Posch_2011, Waldmuller_2010-unpublished poster, Merlo_2013). These data indicate that the variant may be associated with disease. At-least one co-occurrence with other pathogenic variant(s) has been reported (MYH7 c.1988G>A, p.R663H), providing supporting evidence for a benign role (Waldmuller_2010, unpublished poster abstract). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign. -

Hypertrophic cardiomyopathy 14 Uncertain:2Benign:1
-
Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: clinical testing

- -

Jul 24, 2024
Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Wolff-Parkinson-White pattern Pathogenic:1
Jul 14, 2017
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Significance: Likely pathogenic
Review Status: flagged submission
Collection Method: research

This variant was identified in an individual with Wolff-Parkinson-White syndrome -

Dilated cardiomyopathy 1EE Pathogenic:1
Jul 05, 2005
OMIM
Significance: Pathogenic
Review Status: flagged submission
Collection Method: literature only

- -

Hypertrophic cardiomyopathy Uncertain:1
-
Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

- -

Cardiomyopathy Benign:1
Mar 22, 2019
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Primary dilated cardiomyopathy;C0042514:Ventricular tachycardia Benign:1
Mar 04, 2019
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Primary dilated cardiomyopathy Benign:1
Jun 24, 2013
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: research

- -

Cardiovascular phenotype Benign:1
Mar 01, 2019
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.085
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Uncertain
0.010
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.54
D;D
Eigen
Benign
0.054
Eigen_PC
Benign
0.21
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.85
T;.
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.024
T;T
MetaSVM
Uncertain
-0.23
T
MutationAssessor
Uncertain
2.5
M;M
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-2.1
N;N
REVEL
Uncertain
0.55
Sift
Uncertain
0.026
D;D
Sift4G
Benign
0.39
T;T
Polyphen
0.024
B;B
Vest4
0.61
MVP
0.68
MPC
0.34
ClinPred
0.040
T
GERP RS
5.1
Varity_R
0.24
gMVP
0.45

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs143978652; hg19: chr14-23862646; API