rs17817203

chr17-10655059-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002470.4(MYH3):c.6T>C(p.Ser2=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0204 in 1,613,930 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (35 hom., cov: 32)
  • Exomes 𝑓: 0.020 (324 hom.)
• Consequence: MYH3 NM_002470.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.02

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 17-10655059-A-G is Benign according to our data. Variant chr17-10655059-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 129667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10655059-A-G is described in Lovd as [Benign]. Variant chr17-10655059-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.02 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.022 (3348/152132) while in subpopulation AFR AF= 0.031 (1285/41492). AF 95% confidence interval is 0.0296. There are 35 homozygotes in gnomad4. There are 1604 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 3343 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH3	NM_002470.4	c.6T>C	p.Ser2=	synonymous_variant	3/41	ENST00000583535.6
MYH3	XM_011523870.4	c.6T>C	p.Ser2=	synonymous_variant	3/41
MYH3	XM_011523871.3	c.6T>C	p.Ser2=	synonymous_variant	3/41
MYH3	XM_047436127.1	c.6T>C	p.Ser2=	synonymous_variant	5/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH3	ENST00000583535.6	c.6T>C	p.Ser2=	synonymous_variant	3/41	5	NM_002470.4	P1
MYH3	ENST00000582580.1	n.94T>C		non_coding_transcript_exon_variant	3/4	5

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3343 AN: 152014 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.0310

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0138

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.0270

Gnomad FIN AF: 0.0191

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0212

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.0180 AC: 4537 AN: 251470 Hom.: 67 AF XY: 0.0187 AC XY: 2537 AN XY: 135910

Gnomad AFR exome AF: 0.0298

Gnomad AMR exome AF: 0.00781

Gnomad ASJ exome AF: 0.00873

Gnomad EAS exome AF: 0.000870

Gnomad SAS exome AF: 0.0293

Gnomad FIN exome AF: 0.0175

Gnomad NFE exome AF: 0.0201

Gnomad OTH exome AF: 0.0184

GnomAD4 exome AF: 0.0202 AC: 29530 AN: 1461798 Hom.: 324 Cov.: 33 AF XY: 0.0205 AC XY: 14875 AN XY: 727206

Gnomad4 AFR exome AF: 0.0290

Gnomad4 AMR exome AF: 0.00780

Gnomad4 ASJ exome AF: 0.00838

Gnomad4 EAS exome AF: 0.00589

Gnomad4 SAS exome AF: 0.0289

Gnomad4 FIN exome AF: 0.0165

Gnomad4 NFE exome AF: 0.0209

Gnomad4 OTH exome AF: 0.0189

GnomAD4 genome AF: 0.0220 AC: 3348 AN: 152132 Hom.: 35 Cov.: 32 AF XY: 0.0216 AC XY: 1604 AN XY: 74362

Gnomad4 AFR AF: 0.0310

Gnomad4 AMR AF: 0.0137

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00252

Gnomad4 SAS AF: 0.0272

Gnomad4 FIN AF: 0.0191

Gnomad4 NFE AF: 0.0212

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0206 Hom.: 20

Bravo AF: 0.0211

Asia WGS AF: 0.0360 AC: 125 AN: 3478

EpiCase AF: 0.0208

EpiControl AF: 0.0181

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2020	- -

Freeman-Sheldon syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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	-0.68
Cadd	Benign	0.79
Dann	Benign	0.51

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: rs17817203; hg19: chr17-10558376; COSMIC: COSV56870734; COSMIC: COSV56870734;