14-23412741-C-T

Variant names:

• chr14-23412741-C-T
• rs17794387
• NM_000257.4:c.*113G>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.*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
• Publications: 6 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=-0.8).
• BP6: Variant 14-23412741-C-T is Benign according to our data. Variant chr14-23412741-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 312887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0955 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.*113G>A		splice_region	Exon 40 of 40	NP_000248.2
	MYH7	NM_000257.4	MANE Select	c.*113G>A		3_prime_UTR	Exon 40 of 40	NP_000248.2
	MYH7	NM_001407004.1		c.*113G>A		splice_region	Exon 39 of 39	NP_001393933.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.*113G>A		splice_region	Exon 40 of 40	ENSP00000347507.3
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.*113G>A		3_prime_UTR	Exon 40 of 40	ENSP00000347507.3
	MYH7	ENST00000713768.1		c.*162G>A		splice_region	Exon 41 of 41	ENSP00000519070.1

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

African (AFR) AF: 0.0263 AC: 711 AN: 27020

American (AMR) AF: 0.0564 AC: 2331 AN: 41306

Ashkenazi Jewish (ASJ) AF: 0.0933 AC: 2222 AN: 23822

East Asian (EAS) AF: 0.0468 AC: 1754 AN: 37512

South Asian (SAS) AF: 0.105 AC: 8155 AN: 77704

European-Finnish (FIN) AF: 0.0853 AC: 3913 AN: 45854

Middle Eastern (MID) AF: 0.0839 AC: 396 AN: 4720

European-Non Finnish (NFE) AF: 0.0771 AC: 64590 AN: 838252

Other (OTH) AF: 0.0745 AC: 3736 AN: 50152

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

African (AFR) AF: 0.0292 AC: 1212 AN: 41554

American (AMR) AF: 0.0767 AC: 1173 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0884 AC: 307 AN: 3472

East Asian (EAS) AF: 0.0569 AC: 295 AN: 5188

South Asian (SAS) AF: 0.103 AC: 496 AN: 4818

European-Finnish (FIN) AF: 0.0822 AC: 871 AN: 10596

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0772 AC: 5248 AN: 68010

Other (OTH) AF: 0.0701 AC: 148 AN: 2112

Alfa AF: 0.0761 Hom.: 762

Bravo AF: 0.0612

Asia WGS AF: 0.0770 AC: 267 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Dilated Cardiomyopathy, Dominant (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Atrial septal defect (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 1 (1)
-	-	1	Left ventricular noncompaction cardiomyopathy (1)
-	-	1	MYH7-related skeletal myopathy (1)
-	-	1	Myosin storage myopathy (1)
-	-	1	Scapuloperoneal myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.5
DANN	Benign	0.70
PhyloP100		-1.1
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: rs17794387; hg19: chr14-23881950;