rs1383779893

Positions:

• chr14-23389634-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_002471.4(MYH6):​c.3818A>G​(p.Asn1273Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,894 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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: 0.0000048 (1 hom.)
• Consequence: MYH6 NM_002471.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.676

Genes affected

MYH6 (HGNC:7576): (myosin heavy chain 6) Cardiac muscle myosin is a hexamer consisting of two heavy chain subunits, two light chain subunits, and two regulatory subunits. This gene encodes the alpha heavy chain subunit of cardiac myosin. The gene is located approximately 4kb downstream of the gene encoding the beta heavy chain subunit of cardiac myosin. Mutations in this gene cause familial hypertrophic cardiomyopathy and atrial septal defect 3. [provided by RefSeq, Feb 2017]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH6. . Gene score misZ 0.85843 (greater than the threshold 3.09). Trascript score misZ 4.1282 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, hypertrophic cardiomyopathy, Keppen-Lubinsky syndrome, atrial septal defect 3, familial isolated dilated cardiomyopathy, hypertrophic cardiomyopathy 14.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2831415).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH6	NM_002471.4	c.3818A>G	p.Asn1273Ser	missense_variant	27/39	ENST00000405093.9	NP_002462.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH6	ENST00000405093.9	c.3818A>G	p.Asn1273Ser	missense_variant	27/39	5	NM_002471.4	ENSP00000386041.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461894 Hom.: 1 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy 14 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 25, 2020

In summary, this variant is a novel missense change with uncertain impact on protein function and splicing. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MYH6-related disease. This sequence change replaces asparagine with serine at codon 1273 of the MYH6 protein (p.Asn1273Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.86	D;.
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.5	L;L
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.23
Sift	Benign	0.14	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.14	B;B
Vest4		0.17
MutPred		0.50		Gain of phosphorylation at N1273 (P = 0.0285);Gain of phosphorylation at N1273 (P = 0.0285);
MVP		0.81
MPC		0.20
ClinPred		0.17	T
GERP RS		3.7
Varity_R		0.083
gMVP		0.13

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: rs1383779893; hg19: chr14-23858843;