rs779700642

chr17-10652560-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_002470.4(MYH3):c.208C>T(p.Leu70=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,575,466 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00014 (3 hom.)
• Consequence: MYH3 NM_002470.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.252

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 17-10652560-G-A is Benign according to our data. Variant chr17-10652560-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 258672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10652560-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.252 with no splicing effect.
• BS2: High AC in GnomAd at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH3	NM_002470.4	c.208C>T	p.Leu70=	synonymous_variant	4/41	ENST00000583535.6
MYH3	XM_011523870.4	c.208C>T	p.Leu70=	synonymous_variant	4/41
MYH3	XM_011523871.3	c.208C>T	p.Leu70=	synonymous_variant	4/41
MYH3	XM_047436127.1	c.208C>T	p.Leu70=	synonymous_variant	6/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH3	ENST00000583535.6	c.208C>T	p.Leu70=	synonymous_variant	4/41	5	NM_002470.4	P1
MYH3	ENST00000582580.1	n.296C>T		non_coding_transcript_exon_variant	4/4	5

Frequencies

GnomAD3 genomes AF: 0.000128 AC: 19 AN: 148376 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000738

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000267

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000215

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.0000898

Gnomad OTH AF: 0.00196

GnomAD3 exomes AF: 0.000147 AC: 37 AN: 251384 Hom.: 0 AF XY: 0.000191 AC XY: 26 AN XY: 135862

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000139 AC: 199 AN: 1427012 Hom.: 3 Cov.: 36 AF XY: 0.000162 AC XY: 115 AN XY: 709882

Gnomad4 AFR exome AF: 0.000585

Gnomad4 AMR exome AF: 0.000206

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000314

Gnomad4 FIN exome AF: 0.0000198

Gnomad4 NFE exome AF: 0.0000826

Gnomad4 OTH exome AF: 0.000328

GnomAD4 genome AF: 0.000128 AC: 19 AN: 148454 Hom.: 0 Cov.: 31 AF XY: 0.000152 AC XY: 11 AN XY: 72232

Gnomad4 AFR AF: 0.0000736

Gnomad4 AMR AF: 0.000267

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000431

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000898

Gnomad4 OTH AF: 0.00145

Alfa AF: 0.0000683 Hom.: 0

Bravo AF: 0.000113

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000474

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	8.4
Dann	Benign	0.86

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: rs779700642; hg19: chr17-10555877; COSMIC: COSV56863477; COSMIC: COSV56863477;