14-23419456-A-T

Variant names:

• chr14-23419456-A-T
• rs2277475
• NM_000257.4:c.3853+27T>A

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.3853+27T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 1,612,690 control chromosomes in the GnomAD database, including 107,807 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (14385 hom., cov: 31)
  • Exomes 𝑓: 0.35 (93422 hom.)
• Consequence: MYH7 NM_000257.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.406
• Publications: 8 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=-0.97).
• BP6: Variant 14-23419456-A-T is Benign according to our data. Variant chr14-23419456-A-T is described in ClinVar as Benign. ClinVar VariationId is 255629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.625 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000257.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	NM_000257.4	MANE Select	c.3853+27T>A		intron	N/A	NP_000248.2
	MYH7	NM_001407004.1		c.3853+27T>A		intron	N/A	NP_001393933.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.3853+27T>A		intron	N/A	ENSP00000347507.3
	MYH7	ENST00000713768.1		c.3853+27T>A		intron	N/A	ENSP00000519070.1
	MYH7	ENST00000713769.1		c.3853+27T>A		intron	N/A	ENSP00000519071.1

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61834 AN: 151666 Hom.: 14351 Cov.: 31

Gnomad AFR AF: 0.632

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.384

Gnomad EAS AF: 0.0803

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.405

GnomAD2 exomes AF: 0.306 AC: 76783 AN: 250880 AF XY: 0.304

Gnomad AFR exome AF: 0.634

Gnomad AMR exome AF: 0.182

Gnomad ASJ exome AF: 0.395

Gnomad EAS exome AF: 0.0783

Gnomad FIN exome AF: 0.261

Gnomad NFE exome AF: 0.356

Gnomad OTH exome AF: 0.325

GnomAD4 exome AF: 0.347 AC: 506871 AN: 1460906 Hom.: 93422 Cov.: 58 AF XY: 0.343 AC XY: 249329 AN XY: 726800

African (AFR) AF: 0.640 AC: 21430 AN: 33462

American (AMR) AF: 0.197 AC: 8789 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 10402 AN: 26134

East Asian (EAS) AF: 0.0554 AC: 2201 AN: 39700

South Asian (SAS) AF: 0.225 AC: 19361 AN: 86226

European-Finnish (FIN) AF: 0.272 AC: 14382 AN: 52952

Middle Eastern (MID) AF: 0.307 AC: 1688 AN: 5506

European-Non Finnish (NFE) AF: 0.367 AC: 407695 AN: 1111866

Other (OTH) AF: 0.347 AC: 20923 AN: 60342

GnomAD4 genome AF: 0.408 AC: 61902 AN: 151784 Hom.: 14385 Cov.: 31 AF XY: 0.395 AC XY: 29294 AN XY: 74178

African (AFR) AF: 0.632 AC: 26110 AN: 41326

American (AMR) AF: 0.283 AC: 4313 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 1330 AN: 3462

East Asian (EAS) AF: 0.0805 AC: 416 AN: 5170

South Asian (SAS) AF: 0.214 AC: 1029 AN: 4800

European-Finnish (FIN) AF: 0.263 AC: 2779 AN: 10574

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.363 AC: 24615 AN: 67882

Other (OTH) AF: 0.400 AC: 846 AN: 2114

Alfa AF: 0.302 Hom.: 1247

Bravo AF: 0.417

Asia WGS AF: 0.175 AC: 610 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.53
DANN	Benign	0.64
PhyloP100		-0.41
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: rs2277475; hg19: chr14-23888665;