NM_002470.4:c.3009G>A

Variant names:

• chr17-10639391-C-T
• rs61735353
• NM_002470.4:c.3009G>A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_002470.4(MYH3):​c.3009G>A​(p.Ala1003Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 1,614,082 control chromosomes in the GnomAD database, including 210 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (17 hom., cov: 32)
  • Exomes 𝑓: 0.015 (193 hom.)
• Consequence: MYH3 NM_002470.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.470

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 17-10639391-C-T is Benign according to our data. Variant chr17-10639391-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 129655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10639391-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0119 (1817/152286) while in subpopulation NFE AF= 0.0159 (1084/68016). AF 95% confidence interval is 0.0151. There are 17 homozygotes in gnomad4. There are 885 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1817 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4	c.3009G>A	p.Ala1003Ala	synonymous_variant	Exon 24 of 41	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.3009G>A	p.Ala1003Ala	synonymous_variant	Exon 24 of 41		XP_011522172.1
MYH3	XM_011523871.3	c.3009G>A	p.Ala1003Ala	synonymous_variant	Exon 24 of 41		XP_011522173.1
MYH3	XM_047436127.1	c.3009G>A	p.Ala1003Ala	synonymous_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.3009G>A	p.Ala1003Ala	synonymous_variant	Exon 24 of 41	5	NM_002470.4	ENSP00000464317.1

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1819 AN: 152168 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00565

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00779

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0248

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.0119

GnomAD3 exomes AF: 0.0122 AC: 3071 AN: 251226 Hom.: 24 AF XY: 0.0120 AC XY: 1628 AN XY: 135820

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.00509

Gnomad ASJ exome AF: 0.0204

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000882

Gnomad FIN exome AF: 0.0290

Gnomad NFE exome AF: 0.0162

Gnomad OTH exome AF: 0.0152

GnomAD4 exome AF: 0.0149 AC: 21816 AN: 1461796 Hom.: 193 Cov.: 66 AF XY: 0.0143 AC XY: 10427 AN XY: 727192

Gnomad4 AFR exome AF: 0.00493

Gnomad4 AMR exome AF: 0.00532

Gnomad4 ASJ exome AF: 0.0193

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.0302

Gnomad4 NFE exome AF: 0.0165

Gnomad4 OTH exome AF: 0.0141

GnomAD4 genome AF: 0.0119 AC: 1817 AN: 152286 Hom.: 17 Cov.: 32 AF XY: 0.0119 AC XY: 885 AN XY: 74466

Gnomad4 AFR AF: 0.00565

Gnomad4 AMR AF: 0.00778

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0248

Gnomad4 NFE AF: 0.0159

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0145 Hom.: 9

Bravo AF: 0.0106

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0154

EpiControl AF: 0.0138

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Sep 30, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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 13, 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 13, 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
BayesDel_noAF	Benign	-0.37
CADD	Benign	12
DANN	Benign	0.47

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: rs61735353; hg19: chr17-10542708;