rs144957142

chr14-23392607-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_002471.4(MYH6):c.3297G>A(p.Glu1099=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,607,288 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00086 (1 hom., cov: 26)
  • Exomes 𝑓: 0.000097 (1 hom.)
• Consequence: MYH6 NM_002471.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.675

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 14-23392607-C-T is Benign according to our data. Variant chr14-23392607-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 44479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23392607-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.675 with no splicing effect.
• BS2: High AC in GnomAd at 127 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4	c.3297G>A	p.Glu1099=	synonymous_variant	25/39	ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9	c.3297G>A	p.Glu1099=	synonymous_variant	25/39	5	NM_002471.4	P1

Frequencies

GnomAD3 genomes AF: 0.000846 AC: 127 AN: 150072 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.000486

GnomAD3 exomes AF: 0.000262 AC: 66 AN: 251488 Hom.: 1 AF XY: 0.000221 AC XY: 30 AN XY: 135918

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000968 AC: 141 AN: 1457098 Hom.: 1 Cov.: 35 AF XY: 0.000102 AC XY: 74 AN XY: 724784

Gnomad4 AFR exome AF: 0.00276

Gnomad4 AMR exome AF: 0.000337

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.000150

GnomAD4 genome AF: 0.000859 AC: 129 AN: 150190 Hom.: 1 Cov.: 26 AF XY: 0.000860 AC XY: 63 AN XY: 73238

Gnomad4 AFR AF: 0.00301

Gnomad4 AMR AF: 0.000133

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000443

Gnomad4 OTH AF: 0.000481

Alfa AF: 0.000747 Hom.: 0

Bravo AF: 0.000782

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 14, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 30, 2015	p.Glu1099Glu in exon 25 of MYH6: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 0.3% (28/10402) o f African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs144957142). -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	MYH6: BP4, BP7 -

Hypertrophic cardiomyopathy 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2023

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
BayesDel_noAF	Benign	-0.40
Cadd	Benign	1.4
Dann	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144957142; hg19: chr14-23861816;