rs727503247

chr14-23419182-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000257.4(MYH7):c.3967G>A(p.Val1323Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.837

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MYH7
• BP4: Computational evidence support a benign effect (MetaRNN=0.19793421).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.3967G>A	p.Val1323Ile	missense_variant	29/40	ENST00000355349.4
MYH7	NM_001407004.1	c.3967G>A	p.Val1323Ile	missense_variant	28/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.3967G>A	p.Val1323Ile	missense_variant	29/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461812 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 21, 2013

Variant classified as Uncertain Significance - Favor Benign. The Val1323Ile vari ant in MYH7 has now been identified by our laboratory in 1 Caucasian individual with HCM. It has not been identified in large population studies. Valine (Val) a t position 1323 is not conserved in mammals or evolutionarily distant species an d the change to isoleucine (Ile; this variant) has been identified in two fish s pecies. Additionally, this variant was predicted to be benign using a computatio nal tool clinically validated by our laboratory. This tool's benign prediction i s estimated to be correct 89% of the time (Jordan 2011). Although this data supp orts that the Val1323Ile variant may be benign, additional studies are needed to fully assess its clinical significance. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Nov 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
CardioboostCm	Benign	0.029
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.66	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.30	N
MutationTaster	Benign	0.78	N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.22
Sift	Benign	0.38	T
Sift4G	Benign	0.069	T
Polyphen		0.0	B
Vest4		0.032
MutPred		0.32		Gain of ubiquitination at K1324 (P = 0.2106);
MVP		0.79
MPC		0.47
ClinPred		0.22	T
GERP RS		5.0
Varity_R		0.055
gMVP		0.42

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: rs727503247; hg19: chr14-23888391;