14-23412741-C-T

Position:

• chr14-23412741-C-T

Variant summary

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

The NM_000257.4(MYH7):​c.*113G>A variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0753 in 1,298,592 control chromosomes in the GnomAD database, including 3,967 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (399 hom., cov: 32)
  • Exomes 𝑓: 0.077 (3568 hom.)
• Consequence: MYH7 NM_000257.4 splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.10

Genes affected

MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 14-23412741-C-T is Benign according to our data. Variant chr14-23412741-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 312887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23412741-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0955 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.*113G>A		splice_region_variant	40/40	ENST00000355349.4	NP_000248.2
MYH7	NM_000257.4	c.*113G>A		3_prime_UTR_variant	40/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.*113G>A		splice_region_variant	39/39		NP_001393933.1
MYH7	NM_001407004.1	c.*113G>A		3_prime_UTR_variant	39/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.*113G>A		splice_region_variant	40/40	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000355349	c.*113G>A		3_prime_UTR_variant	40/40	1	NM_000257.4	ENSP00000347507.3

Frequencies

GnomAD3 genomes AF: 0.0659 AC: 10028 AN: 152130 Hom.: 400 Cov.: 32

Gnomad AFR AF: 0.0293

Gnomad AMI AF: 0.272

Gnomad AMR AF: 0.0768

Gnomad ASJ AF: 0.0884

Gnomad EAS AF: 0.0565

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0822

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0772

Gnomad OTH AF: 0.0713

GnomAD4 exome AF: 0.0766 AC: 87808 AN: 1146342 Hom.: 3568 Cov.: 15 AF XY: 0.0783 AC XY: 45604 AN XY: 582680

Gnomad4 AFR exome AF: 0.0263

Gnomad4 AMR exome AF: 0.0564

Gnomad4 ASJ exome AF: 0.0933

Gnomad4 EAS exome AF: 0.0468

Gnomad4 SAS exome AF: 0.105

Gnomad4 FIN exome AF: 0.0853

Gnomad4 NFE exome AF: 0.0771

Gnomad4 OTH exome AF: 0.0745

GnomAD4 genome AF: 0.0658 AC: 10020 AN: 152250 Hom.: 399 Cov.: 32 AF XY: 0.0660 AC XY: 4910 AN XY: 74432

Gnomad4 AFR AF: 0.0292

Gnomad4 AMR AF: 0.0767

Gnomad4 ASJ AF: 0.0884

Gnomad4 EAS AF: 0.0569

Gnomad4 SAS AF: 0.103

Gnomad4 FIN AF: 0.0822

Gnomad4 NFE AF: 0.0772

Gnomad4 OTH AF: 0.0701

Alfa AF: 0.0778 Hom.: 638

Bravo AF: 0.0612

Asia WGS AF: 0.0770 AC: 267 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Dilated Cardiomyopathy, Dominant Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Scapuloperoneal myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

MYH7-related skeletal myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Myosin storage myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Atrial septal defect Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Left ventricular noncompaction cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypertrophic cardiomyopathy 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.5
DANN	Benign	0.70

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: rs17794387; hg19: chr14-23881950;