17-10496580-A-G

Variant names:

• chr17-10496580-A-G
• rs3744563
• NM_005963.4:c.4657-31T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005963.4(MYH1):​c.4657-31T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 1,613,346 control chromosomes in the GnomAD database, including 163,693 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.43 (14636 hom., cov: 31)
  • Exomes 𝑓: 0.44 (149057 hom.)
• Consequence: MYH1 NM_005963.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0650
• Publications: 6 publications found

Genes affected

MYH1 (HGNC:7567): (myosin heavy chain 1) Myosin is a major contractile protein which converts chemical energy into mechanical energy through the hydrolysis of ATP. Myosin is a hexameric protein composed of a pair of myosin heavy chains (MYH) and two pairs of nonidentical light chains. Myosin heavy chains are encoded by a multigene family. In mammals at least 10 different myosin heavy chain (MYH) isoforms have been described from striated, smooth, and nonmuscle cells. These isoforms show expression that is spatially and temporally regulated during development. [provided by RefSeq, Jul 2008]

MYHAS (HGNC:50609): (myosin heavy chain gene cluster antisense RNA) Predicted to enable primary miRNA binding activity. Predicted to be involved in response to muscle activity and skeletal muscle fiber development. Predicted to act upstream of or within with a positive effect on gene expression. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.835 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH1	NM_005963.4	c.4657-31T>C		intron_variant	Intron 33 of 39	ENST00000226207.6	NP_005954.3
MYHAS	NR_125367.1	n.168-70957A>G		intron_variant	Intron 2 of 10
MYH1	XM_017024675.2	c.4657-31T>C		intron_variant	Intron 33 of 39		XP_016880164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH1	ENST00000226207.6	c.4657-31T>C		intron_variant	Intron 33 of 39	5	NM_005963.4	ENSP00000226207.5

Frequencies

GnomAD3 genomes AF: 0.425 AC: 64578 AN: 151784 Hom.: 14628 Cov.: 31

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.480

Gnomad AMR AF: 0.493

Gnomad ASJ AF: 0.459

Gnomad EAS AF: 0.857

Gnomad SAS AF: 0.638

Gnomad FIN AF: 0.480

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.413

Gnomad OTH AF: 0.394

GnomAD2 exomes AF: 0.500 AC: 125201 AN: 250176 AF XY: 0.500

Gnomad AFR exome AF: 0.321

Gnomad AMR exome AF: 0.607

Gnomad ASJ exome AF: 0.460

Gnomad EAS exome AF: 0.874

Gnomad FIN exome AF: 0.478

Gnomad NFE exome AF: 0.410

Gnomad OTH exome AF: 0.457

GnomAD4 exome AF: 0.441 AC: 644394 AN: 1461444 Hom.: 149057 Cov.: 41 AF XY: 0.445 AC XY: 323792 AN XY: 727076

African (AFR) AF: 0.319 AC: 10664 AN: 33476

American (AMR) AF: 0.590 AC: 26379 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 12056 AN: 26134

East Asian (EAS) AF: 0.843 AC: 33467 AN: 39698

South Asian (SAS) AF: 0.620 AC: 53476 AN: 86244

European-Finnish (FIN) AF: 0.467 AC: 24899 AN: 53370

Middle Eastern (MID) AF: 0.439 AC: 2533 AN: 5768

European-Non Finnish (NFE) AF: 0.408 AC: 453575 AN: 1111650

Other (OTH) AF: 0.453 AC: 27345 AN: 60384

GnomAD4 genome AF: 0.425 AC: 64625 AN: 151902 Hom.: 14636 Cov.: 31 AF XY: 0.439 AC XY: 32554 AN XY: 74232

African (AFR) AF: 0.326 AC: 13508 AN: 41436

American (AMR) AF: 0.493 AC: 7527 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 1593 AN: 3470

East Asian (EAS) AF: 0.856 AC: 4409 AN: 5148

South Asian (SAS) AF: 0.638 AC: 3069 AN: 4810

European-Finnish (FIN) AF: 0.480 AC: 5049 AN: 10512

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.413 AC: 28075 AN: 67956

Other (OTH) AF: 0.394 AC: 830 AN: 2106

Alfa AF: 0.413 Hom.: 3995

Bravo AF: 0.419

Asia WGS AF: 0.689 AC: 2395 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	8.5
DANN	Benign	0.69
PhyloP100		-0.065
Mutation Taster		=100/0	polymorphism (auto)

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: rs3744563; hg19: chr17-10399897; COSMIC: COSV56845662;