rs28730771

chr14-23390401-C-Achr14-23390401-C-Gchr14-23390401-C-T

Variant summary

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

The NM_002471.4(MYH6):c.3388G>T(p.Ala1130Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1130T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH6 NM_002471.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.899

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 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, MYH6
• BP4: Computational evidence support a benign effect (MetaRNN=0.19730216).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH6	NM_002471.4	c.3388G>T	p.Ala1130Ser	missense_variant	26/39	ENST00000405093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH6	ENST00000405093.9	c.3388G>T	p.Ala1130Ser	missense_variant	26/39	5	NM_002471.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000410 AC: 1 AN: 243682 Hom.: 0 AF XY: 0.00000754 AC XY: 1 AN XY: 132668

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000274 AC: 4 AN: 1457832 Hom.: 0 Cov.: 37 AF XY: 0.00000276 AC XY: 2 AN XY: 725158

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: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.38	T;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.68	T;.
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.83	N;N
REVEL	Benign	0.14
Sift	Benign	0.40	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.051	B;B
Vest4		0.30
MutPred		0.50		Gain of phosphorylation at A1130 (P = 0.0013);Gain of phosphorylation at A1130 (P = 0.0013);
MVP		0.80
MPC		2.1
ClinPred		0.18	T
GERP RS		3.4
Varity_R		0.040
gMVP		0.43

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: rs28730771; hg19: chr14-23859610;