rs28730764

chr14-23386148-T-Achr14-23386148-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002471.4(MYH6):c.4960-17A>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,613,188 control chromosomes in the GnomAD database, including 606 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (319 hom., cov: 31)
  • Exomes 𝑓: 0.0080 (287 hom.)
• Consequence: MYH6 NM_002471.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.63

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 14-23386148-T-A is Benign according to our data. Variant chr14-23386148-T-A is described in ClinVar as [Benign]. Clinvar id is 36632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23386148-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4	c.4960-17A>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9	c.4960-17A>T		splice_polypyrimidine_tract_variant, intron_variant		5	NM_002471.4	P1

Frequencies

GnomAD3 genomes AF: 0.0374 AC: 5654 AN: 151216 Hom.: 319 Cov.: 31

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.00174

Gnomad EAS AF: 0.0173

Gnomad SAS AF: 0.00732

Gnomad FIN AF: 0.0000953

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.00485

Gnomad OTH AF: 0.0264

GnomAD3 exomes AF: 0.0137 AC: 3427 AN: 250952 Hom.: 142 AF XY: 0.0113 AC XY: 1530 AN XY: 135654

Gnomad AFR exome AF: 0.127

Gnomad AMR exome AF: 0.00941

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.0169

Gnomad SAS exome AF: 0.00644

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00386

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.00801 AC: 11715 AN: 1461852 Hom.: 287 Cov.: 35 AF XY: 0.00745 AC XY: 5421 AN XY: 727220

Gnomad4 AFR exome AF: 0.119

Gnomad4 AMR exome AF: 0.0106

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.0127

Gnomad4 SAS exome AF: 0.00639

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.00480

Gnomad4 OTH exome AF: 0.0128

GnomAD4 genome AF: 0.0375 AC: 5671 AN: 151336 Hom.: 319 Cov.: 31 AF XY: 0.0360 AC XY: 2664 AN XY: 73948

Gnomad4 AFR AF: 0.120

Gnomad4 AMR AF: 0.0145

Gnomad4 ASJ AF: 0.00174

Gnomad4 EAS AF: 0.0174

Gnomad4 SAS AF: 0.00733

Gnomad4 FIN AF: 0.0000953

Gnomad4 NFE AF: 0.00486

Gnomad4 OTH AF: 0.0261

Alfa AF: 0.0166 Hom.: 14

Bravo AF: 0.0429

Asia WGS AF: 0.0130 AC: 47 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2016	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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 29, 2019	Variant summary: MYH6 c.4960-17A>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational 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 0.014 in 250952 control chromosomes in the gnomAD database, including 142 homozygotes. The observed variant frequency is approximately 546 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 benign. To our knowledge, no occurrence of c.4960-17A>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypertrophic cardiomyopathy 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.22
Dann	Benign	0.58

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: rs28730764; hg19: chr14-23855357; COSMIC: COSV62451107; COSMIC: COSV62451107;