chr17-10639392-G-A

Variant names:

• chr17-10639392-G-A
• rs34088014
• NM_002470.4:c.3008C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002470.4(MYH3):​c.3008C>T​(p.Ala1003Val) variant causes a missense change. The variant allele was found at a frequency of 0.0204 in 1,614,002 control chromosomes in the GnomAD database, including 359 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1003S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (34 hom., cov: 32)
  • Exomes 𝑓: 0.020 (325 hom.)
• Consequence: MYH3 NM_002470.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 5.86
• Publications: 11 publications found

Genes affected

MYH3 (HGNC:7573): (myosin heavy chain 3) 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. This gene is a member of the MYH family and encodes a protein with an IQ domain and a myosin head-like domain. Mutations in this gene have been associated with two congenital contracture (arthrogryposis) syndromes, Freeman-Sheldon syndrome and Sheldon-Hall syndrome. [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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007245183).
• BP6: Variant 17-10639392-G-A is Benign according to our data. Variant chr17-10639392-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0218 (3324/152216) while in subpopulation AFR AF = 0.0309 (1283/41534). AF 95% confidence interval is 0.0295. There are 34 homozygotes in GnomAd4. There are 1590 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4	c.3008C>T	p.Ala1003Val	missense_variant	Exon 24 of 41	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.3008C>T	p.Ala1003Val	missense_variant	Exon 24 of 41		XP_011522172.1
MYH3	XM_011523871.3	c.3008C>T	p.Ala1003Val	missense_variant	Exon 24 of 41		XP_011522173.1
MYH3	XM_047436127.1	c.3008C>T	p.Ala1003Val	missense_variant	Exon 26 of 43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.3008C>T	p.Ala1003Val	missense_variant	Exon 24 of 41	5	NM_002470.4	ENSP00000464317.1
MYHAS	ENST00000579914.2	n.705+25515G>A		intron_variant	Intron 4 of 4	4
MYHAS	ENST00000584139.2	n.1041+25515G>A		intron_variant	Intron 7 of 8	3

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3318 AN: 152098 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.0268

Gnomad FIN AF: 0.0192

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0210

Gnomad OTH AF: 0.0210

GnomAD2 exomes AF: 0.0181 AC: 4540 AN: 251224 AF XY: 0.0187

Gnomad AFR exome AF: 0.0300

Gnomad AMR exome AF: 0.00781

Gnomad ASJ exome AF: 0.00873

Gnomad EAS exome AF: 0.000980

Gnomad FIN exome AF: 0.0176

Gnomad NFE exome AF: 0.0201

Gnomad OTH exome AF: 0.0188

GnomAD4 exome AF: 0.0202 AC: 29558 AN: 1461786 Hom.: 325 Cov.: 66 AF XY: 0.0205 AC XY: 14875 AN XY: 727192

African (AFR) AF: 0.0284 AC: 950 AN: 33478

American (AMR) AF: 0.00798 AC: 357 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00838 AC: 219 AN: 26136

East Asian (EAS) AF: 0.00592 AC: 235 AN: 39698

South Asian (SAS) AF: 0.0288 AC: 2486 AN: 86250

European-Finnish (FIN) AF: 0.0165 AC: 884 AN: 53420

Middle Eastern (MID) AF: 0.00782 AC: 45 AN: 5756

European-Non Finnish (NFE) AF: 0.0209 AC: 23224 AN: 1111938

Other (OTH) AF: 0.0192 AC: 1158 AN: 60396

GnomAD4 genome AF: 0.0218 AC: 3324 AN: 152216 Hom.: 34 Cov.: 32 AF XY: 0.0214 AC XY: 1590 AN XY: 74434

African (AFR) AF: 0.0309 AC: 1283 AN: 41534

American (AMR) AF: 0.0130 AC: 199 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5176

South Asian (SAS) AF: 0.0270 AC: 130 AN: 4814

European-Finnish (FIN) AF: 0.0192 AC: 203 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0210 AC: 1426 AN: 68030

Other (OTH) AF: 0.0222 AC: 47 AN: 2116

Alfa AF: 0.0201 Hom.: 101

Bravo AF: 0.0209

ESP6500AA AF: 0.0293 AC: 129

ESP6500EA AF: 0.0206 AC: 177

ExAC AF: 0.0193 AC: 2338

Asia WGS AF: 0.0370 AC: 129 AN: 3478

EpiCase AF: 0.0208

EpiControl AF: 0.0181

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Freeman-Sheldon syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Distal arthrogryposis type 2B1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.9
PrimateAI	Uncertain	0.68	T
Sift4G	Benign	0.26	T
Polyphen		0.015	B
Vest4		0.097
MPC		0.88
ClinPred		0.016	T
GERP RS		5.5
Varity_R		0.35
gMVP		0.44
Mutation Taster		=87/13	polymorphism (auto)

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: rs34088014; hg19: chr17-10542709; COSMIC: COSV56860370;