rs796313537

Variant names:

• chr14-23389060-GGA-G
• rs796313537
• NM_002471.4:c.3979-7_3979-6delTC

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_002471.4(MYH6):​c.3979-7_3979-6delTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 121,160 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00062 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH6 NM_002471.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -0.131

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 -9 ACMG points.

• BP6: Variant 14-23389060-GGA-G is Benign according to our data. Variant chr14-23389060-GGA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44498.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000289 (35/121160) while in subpopulation AFR AF= 0.00151 (29/19236). AF 95% confidence interval is 0.00108. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH6	NM_002471.4	c.3979-7_3979-6delTC		splice_region_variant, intron_variant	Intron 28 of 38	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9	c.3979-7_3979-6delTC		splice_region_variant, intron_variant	Intron 28 of 38	5	NM_002471.4	ENSP00000386041.3

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 35 AN: 121102 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000712

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000299

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000320

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000542 AC: 10 AN: 184396 Hom.: 0 AF XY: 0.0000396 AC XY: 4 AN XY: 101078

Gnomad AFR exome AF: 0.000848

Gnomad AMR exome AF: 0.0000664

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000577

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000118

Gnomad OTH exome AF: 0.000220

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000618 AC: 880 AN: 1424558 Hom.: 0 AF XY: 0.000608 AC XY: 430 AN XY: 706840

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.0000461

Gnomad4 ASJ exome AF: 0.000560

Gnomad4 EAS exome AF: 0.0000763

Gnomad4 SAS exome AF: 0.0000594

Gnomad4 FIN exome AF: 0.0000408

Gnomad4 NFE exome AF: 0.000749

Gnomad4 OTH exome AF: 0.000577

GnomAD4 genome AF: 0.000289 AC: 35 AN: 121160 Hom.: 0 Cov.: 26 AF XY: 0.000319 AC XY: 19 AN XY: 59560

Gnomad4 AFR AF: 0.00151

Gnomad4 AMR AF: 0.0000710

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000299

Gnomad4 NFE AF: 0.0000320

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Jun 11, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Cardiomyopathy Uncertain:1

Jul 26, 2018

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 14 Benign:1

Oct 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MYH6-related disorder Benign:1

May 26, 2020

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 v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs796313537; hg19: chr14-23858269;