17-10492430-T-C

Variant names:

• chr17-10492430-T-C
• rs2142249922
• NM_005963.4:c.5806A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005963.4(MYH1):​c.5806A>G​(p.Ile1936Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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: 0.0000034 (0 hom.)
• Consequence: MYH1 NM_005963.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.979
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05409527).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH1	NM_005963.4	c.5806A>G	p.Ile1936Val	missense_variant	Exon 40 of 40	ENST00000226207.6	NP_005954.3
MYH1	XM_017024675.2	c.5806A>G	p.Ile1936Val	missense_variant	Exon 40 of 40		XP_016880164.1
MYHAS	NR_125367.1	n.168-75107T>C		intron_variant	Intron 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH1	ENST00000226207.6	c.5806A>G	p.Ile1936Val	missense_variant	Exon 40 of 40	5	NM_005963.4	ENSP00000226207.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461572 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727078

African (AFR) AF: 0.0000299 AC: 1 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111938

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5806A>G (p.I1936V) alteration is located in exon 40 (coding exon 38) of the MYH1 gene. This alteration results from a A to G substitution at nucleotide position 5806, causing the isoleucine (I) at amino acid position 1936 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Uncertain	0.97
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.98
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.23
Sift	Benign	0.36	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.073		Gain of MoRF binding (P = 0.0893);
MVP		0.56
MPC		0.076
ClinPred		0.11	T
GERP RS		4.6
Varity_R		0.053
gMVP		0.061
Mutation Taster		=97/3	polymorphism

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: rs2142249922; hg19: chr17-10395747;