rs555976716

chr14-23389063-G-Achr14-23389063-G-Cchr14-23389063-G-T

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.3979-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 64,952 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (17 hom., cov: 0)
  • Exomes 𝑓: 0.0050 (23 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH6 NM_002471.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00007639
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.275

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=-0.75).
• BP6: Variant 14-23389063-G-A is Benign according to our data. Variant chr14-23389063-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 196173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23389063-G-A is described in Lovd as [Benign]. Variant chr14-23389063-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4	c.3979-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9	c.3979-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_002471.4	P1

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 1146 AN: 64966 Hom.: 17 Cov.: 0

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0212

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0217

Gnomad NFE AF: 0.000483

Gnomad OTH AF: 0.0128

GnomAD3 exomes AF: 0.00483 AC: 737 AN: 152678 Hom.: 9 AF XY: 0.00486 AC XY: 406 AN XY: 83470

Gnomad AFR exome AF: 0.0272

Gnomad AMR exome AF: 0.00393

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000283

Gnomad SAS exome AF: 0.0139

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000428

Gnomad OTH exome AF: 0.00483

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00502 AC: 2166 AN: 431174 Hom.: 23 Cov.: 0 AF XY: 0.00576 AC XY: 1213 AN XY: 210770

Gnomad4 AFR exome AF: 0.0791

Gnomad4 AMR exome AF: 0.00967

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000316

Gnomad4 SAS exome AF: 0.0348

Gnomad4 FIN exome AF: 0.000161

Gnomad4 NFE exome AF: 0.000728

Gnomad4 OTH exome AF: 0.0103

GnomAD4 genome AF: 0.0177 AC: 1148 AN: 64952 Hom.: 17 Cov.: 0 AF XY: 0.0173 AC XY: 554 AN XY: 32112

Gnomad4 AFR AF: 0.176

Gnomad4 AMR AF: 0.0116

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0213

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000483

Gnomad4 OTH AF: 0.0127

Bravo AF: 0.00885

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 28, 2023	- -

Hypertrophic cardiomyopathy 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 05, 2016

- -

Dilated cardiomyopathy 1EE;C2750467:Hypertrophic cardiomyopathy 14;C3279790:Atrial septal defect 3;C3279791:Sick sinus syndrome 3, susceptibility to;C3495498:Hypertrophic cardiomyopathy 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	2.1
Dann	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000076
dbscSNV1_RF	Benign	0.0040
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: rs555976716; hg19: chr14-23858272;