17-10496144-G-T

Variant names:

• chr17-10496144-G-T
• rs142545737
• NM_005963.4:c.4975C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_005963.4(MYH1):​c.4975C>A​(p.Leu1659Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,612,070 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: MYH1 NM_005963.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.22
• Publications: 2 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00853157).
• BP6: Variant 17-10496144-G-T is Benign according to our data. Variant chr17-10496144-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 2353820.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH1	NM_005963.4	c.4975C>A	p.Leu1659Ile	missense_variant	Exon 35 of 40	ENST00000226207.6	NP_005954.3
MYH1	XM_017024675.2	c.4975C>A	p.Leu1659Ile	missense_variant	Exon 35 of 40		XP_016880164.1
MYHAS	NR_125367.1	n.168-71393G>T		intron_variant	Intron 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH1	ENST00000226207.6	c.4975C>A	p.Leu1659Ile	missense_variant	Exon 35 of 40	5	NM_005963.4	ENSP00000226207.5

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152164 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000195 AC: 49 AN: 251156 AF XY: 0.000206

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000103 AC: 150 AN: 1459788 Hom.: 1 Cov.: 31 AF XY: 0.000105 AC XY: 76 AN XY: 726196

African (AFR) AF: 0.000478 AC: 16 AN: 33466

American (AMR) AF: 0.0000676 AC: 3 AN: 44366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39500

South Asian (SAS) AF: 0.000919 AC: 79 AN: 85958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000378 AC: 42 AN: 1110968

Other (OTH) AF: 0.000166 AC: 10 AN: 60316

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152282 Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11 AN XY: 74464

African (AFR) AF: 0.000433 AC: 18 AN: 41574

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000581 Hom.: 0

Bravo AF: 0.000246

ExAC AF: 0.000264 AC: 32

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 16, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	2.0
DANN	Benign	0.69
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.73	N
PhyloP100		-2.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.19
Sift	Benign	0.40	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.073
MVP		0.31
MPC		0.10
ClinPred		0.010	T
GERP RS		-11
Varity_R		0.056
gMVP		0.040
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs142545737; hg19: chr17-10399461; COSMIC: COSV56843930;