rs201307101

Variant names:

• chr14-23417295-C-A
• rs201307101
• NM_000257.4:c.4377G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-23417295-C-A
• chr14-23417295-C-T
• chr14-23417295-C-G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. BS1 PP3

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.4377G>T (p.Lys1459Asn) variant in the MYH7 gene is 0.0375% (34/66566) of European chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; PMID:29300372). Additionally, while computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3), this pathogenic evidence code (PP3) was not considered to be in conflict with a likely benign conclusion given the accuracy of computation prediction tools. In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PP3; BS1 LINK:https://erepo.genome.network/evrepo/ui/classification/CA014901/MONDO:0004994/002

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Likely benign reviewed by expert panel P:4 U:13 B:9
• Conservation: PhyloP100: 1.07
• Publications: 23 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]

MHRT (HGNC:51291): (myosin heavy chain associated RNA transcript) This gene encodes a spliced long non-coding RNA that may act as a cardioprotective agent in the heart. Based on a study of a similar gene in mouse, the encoded transcript may regulate chromatin remodeling by acting as a decoy to the BRG1 chromatin repressor complex thus preventing it from binding to its genomic targets. Blocking the actions of BRG1 could be crucial in protecting the heart from pathological hypertrophy. [provided by RefSeq, Dec 2014]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	NM_000257.4	MANE Select	c.4377G>T	p.Lys1459Asn	missense	Exon 32 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.4377G>T	p.Lys1459Asn	missense	Exon 31 of 39	NP_001393933.1	P12883
	MHRT	NR_126491.1		n.735C>A		non_coding_transcript_exon	Exon 5 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.4377G>T	p.Lys1459Asn	missense	Exon 32 of 40	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.4377G>T	p.Lys1459Asn	missense	Exon 32 of 40	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.4377G>T	p.Lys1459Asn	missense	Exon 32 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000299 AC: 75 AN: 251252 AF XY: 0.000331

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000555

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000482 AC: 704 AN: 1461804 Hom.: 0 Cov.: 34 AF XY: 0.000433 AC XY: 315 AN XY: 727206

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.000594 AC: 660 AN: 1112012

Other (OTH) AF: 0.000397 AC: 24 AN: 60394

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15 AN XY: 74370

African (AFR) AF: 0.000169 AC: 7 AN: 41452

American (AMR) AF: 0.000327 AC: 5 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000126 Hom.: 0

Bravo AF: 0.000242

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000305 AC: 37

EpiCase AF: 0.000491

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	4	-	not provided (5)
-	2	2	Cardiomyopathy (4)
1	2	1	Hypertrophic cardiomyopathy 1 (4)
-	1	2	not specified (3)
-	1	1	Hypertrophic cardiomyopathy (2)
1	1	-	Primary familial hypertrophic cardiomyopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Congenital myopathy with fiber type disproportion (1)
-	-	1	Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy (1)
-	-	1	MYH7-related skeletal myopathy (1)
-	1	-	Myosin storage myopathy (1)
1	-	-	Wolff-Parkinson-White pattern (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
CardioboostCm	Uncertain	0.46
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		1.1
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.064	T
Polyphen		1.0	D
Vest4		0.90
MutPred		0.63		Loss of ubiquitination at K1459 (P = 0.0056)
MVP		0.93
MPC		1.7
ClinPred		0.31	T
GERP RS		1.3
Varity_R		0.51
gMVP		0.97
Mutation Taster		=18/82	disease causing

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: rs201307101; hg19: chr14-23886504;