rs779700642

Variant names:

• chr17-10652560-G-A
• rs779700642
• NM_002470.4:c.208C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_002470.4(MYH3):​c.208C>T​(p.Leu70Leu) 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
• Publications: 2 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 -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 VariationId is 258672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.252 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002470.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	NM_002470.4	MANE Select	c.208C>T	p.Leu70Leu	synonymous	Exon 4 of 41	NP_002461.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	ENST00000583535.6	TSL:5 MANE Select	c.208C>T	p.Leu70Leu	synonymous	Exon 4 of 41	ENSP00000464317.1
	MYH3	ENST00000582580.1	TSL:5	n.296C>T		non_coding_transcript_exon	Exon 4 of 4
	MYHAS	ENST00000579914.2	TSL:4	n.706-31375G>A		intron	N/A

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

GnomAD2 exomes AF: 0.000147 AC: 37 AN: 251384 AF XY: 0.000191

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 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

African (AFR) AF: 0.000585 AC: 19 AN: 32498

American (AMR) AF: 0.000206 AC: 9 AN: 43758

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24782

East Asian (EAS) AF: 0.00 AC: 0 AN: 37300

South Asian (SAS) AF: 0.000314 AC: 27 AN: 85934

European-Finnish (FIN) AF: 0.0000198 AC: 1 AN: 50414

Middle Eastern (MID) AF: 0.00636 AC: 34 AN: 5350

European-Non Finnish (NFE) AF: 0.0000826 AC: 90 AN: 1089078

Other (OTH) AF: 0.000328 AC: 19 AN: 57898

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

African (AFR) AF: 0.0000736 AC: 3 AN: 40760

American (AMR) AF: 0.000267 AC: 4 AN: 14982

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.00 AC: 0 AN: 5012

South Asian (SAS) AF: 0.000431 AC: 2 AN: 4642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9556

Middle Eastern (MID) AF: 0.00352 AC: 1 AN: 284

European-Non Finnish (NFE) AF: 0.0000898 AC: 6 AN: 66838

Other (OTH) AF: 0.00145 AC: 3 AN: 2062

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

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	8.4
DANN	Benign	0.86
PhyloP100		0.25
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

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