14-23418398-G-C

Variant names:

• chr14-23418398-G-C
• NM_000257.4:c.3981C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1 PM2 PP2 PP3_Moderate

The NM_000257.4(MYH7):​c.3981C>G​(p.Asn1327Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.31

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 Likely_pathogenic. Variant got 9 ACMG points.

• PS1: Transcript NM_000257.4 (MYH7) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the MYH7 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 341 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 3.9329 (above the threshold of 3.09). Trascript score misZ: 6.7889 (above the threshold of 3.09). GenCC associations: The gene is linked to hyaline body myopathy, MYH7-related skeletal myopathy, dilated cardiomyopathy 1S, congenital myopathy 7A, myosin storage, autosomal dominant, dilated cardiomyopathy, left ventricular noncompaction, myopathy, myosin storage, autosomal dominant, hypertrophic cardiomyopathy, congenital heart disease, Ebstein anomaly, arrhythmogenic right ventricular cardiomyopathy, myopathy, myosin storage, autosomal recessive, hypertrophic cardiomyopathy 1, familial isolated dilated cardiomyopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.3981C>G	p.Asn1327Lys	missense_variant	Exon 30 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.3981C>G	p.Asn1327Lys	missense_variant	Exon 29 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.3981C>G	p.Asn1327Lys	missense_variant	Exon 30 of 40	1	NM_000257.4	ENSP00000347507.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454012 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722036

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: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
CardioboostCm	Uncertain	0.14
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.91	T
Polyphen		0.53	P
Vest4		0.92
MutPred		0.58		Gain of ubiquitination at N1327 (P = 0.0267);
MVP		0.94
MPC		0.97
ClinPred		0.72	D
GERP RS		-0.39
Varity_R		0.25
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-23887607;