NM_000257.4:c.5791-106A>C

Variant names:

• chr14-23412977-T-G
• rs7149517
• NM_000257.4:c.5791-106A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000257.4(MYH7):​c.5791-106A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 1,181,558 control chromosomes in the GnomAD database, including 81,528 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (15798 hom., cov: 32)
  • Exomes 𝑓: 0.34 (65730 hom.)
• Consequence: MYH7 NM_000257.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.27
• Publications: 4 publications found

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]

MYH7 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1S

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• MYH7-related skeletal myopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• myopathy, myosin storage, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• myopathy, myosin storage, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• congenital myopathy 7A, myosin storage, autosomal dominant

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ebstein anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hyaline body myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 14-23412977-T-G is Benign according to our data. Variant chr14-23412977-T-G is described in ClinVar as Benign. ClinVar VariationId is 671943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.5791-106A>C		intron_variant	Intron 39 of 39	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.5791-106A>C		intron_variant	Intron 38 of 38		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.5791-106A>C		intron_variant	Intron 39 of 39	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1	c.*32-106A>C		intron_variant	Intron 40 of 40			ENSP00000519070.1
MYH7	ENST00000713769.1	c.5791-106A>C		intron_variant	Intron 38 of 38			ENSP00000519071.1

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64264 AN: 151922 Hom.: 15764 Cov.: 32

Gnomad AFR AF: 0.677

Gnomad AMI AF: 0.432

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.391

Gnomad EAS AF: 0.0684

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.417

GnomAD4 exome AF: 0.344 AC: 354105 AN: 1029520 Hom.: 65730 AF XY: 0.340 AC XY: 179768 AN XY: 528762

African (AFR) AF: 0.680 AC: 16926 AN: 24882

American (AMR) AF: 0.206 AC: 8187 AN: 39830

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 9395 AN: 23304

East Asian (EAS) AF: 0.0456 AC: 1677 AN: 36802

South Asian (SAS) AF: 0.239 AC: 18129 AN: 75820

European-Finnish (FIN) AF: 0.275 AC: 11638 AN: 42388

Middle Eastern (MID) AF: 0.314 AC: 1552 AN: 4938

European-Non Finnish (NFE) AF: 0.368 AC: 270283 AN: 735128

Other (OTH) AF: 0.351 AC: 16318 AN: 46428

GnomAD4 genome AF: 0.423 AC: 64333 AN: 152038 Hom.: 15798 Cov.: 32 AF XY: 0.410 AC XY: 30439 AN XY: 74326

African (AFR) AF: 0.677 AC: 28091 AN: 41480

American (AMR) AF: 0.292 AC: 4455 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 1355 AN: 3466

East Asian (EAS) AF: 0.0686 AC: 355 AN: 5176

South Asian (SAS) AF: 0.229 AC: 1102 AN: 4816

European-Finnish (FIN) AF: 0.263 AC: 2779 AN: 10568

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.366 AC: 24839 AN: 67938

Other (OTH) AF: 0.412 AC: 870 AN: 2112

Alfa AF: 0.407 Hom.: 1725

Bravo AF: 0.434

Asia WGS AF: 0.184 AC: 642 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.35
DANN	Benign	0.62
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7149517; hg19: chr14-23882186;