NM_002470.4:c.2151C>A

Variant names:

• chr17-10641099-G-T
• rs876657
• NM_002470.4:c.2151C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002470.4(MYH3):​c.2151C>A​(p.Gly717Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 1,604,760 control chromosomes in the GnomAD database, including 377,892 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G717G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.57 (27839 hom., cov: 32)
  • Exomes 𝑓: 0.69 (350053 hom.)
• Consequence: MYH3 NM_002470.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -3.23
• Publications: 19 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 17-10641099-G-T is Benign according to our data. Variant chr17-10641099-G-T is described in ClinVar as Benign. ClinVar VariationId is 129649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.729 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	NM_002470.4	MANE Select	c.2151C>A	p.Gly717Gly	synonymous	Exon 19 of 41	NP_002461.2	P11055

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	ENST00000583535.6	TSL:5 MANE Select	c.2151C>A	p.Gly717Gly	synonymous	Exon 19 of 41	ENSP00000464317.1	P11055
	MYH3	ENST00000961194.1		c.2151C>A	p.Gly717Gly	synonymous	Exon 18 of 40	ENSP00000631253.1
	MYHAS	ENST00000579914.2	TSL:4	n.705+27222G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.574 AC: 87116 AN: 151862 Hom.: 27832 Cov.: 32

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.743

Gnomad AMR AF: 0.562

Gnomad ASJ AF: 0.704

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.522

Gnomad FIN AF: 0.707

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.734

Gnomad OTH AF: 0.590

GnomAD2 exomes AF: 0.610 AC: 153053 AN: 250886 AF XY: 0.622

Gnomad AFR exome AF: 0.293

Gnomad AMR exome AF: 0.467

Gnomad ASJ exome AF: 0.707

Gnomad EAS exome AF: 0.361

Gnomad FIN exome AF: 0.715

Gnomad NFE exome AF: 0.728

Gnomad OTH exome AF: 0.653

GnomAD4 exome AF: 0.686 AC: 996065 AN: 1452780 Hom.: 350053 Cov.: 35 AF XY: 0.684 AC XY: 494939 AN XY: 723260

African (AFR) AF: 0.277 AC: 9218 AN: 33324

American (AMR) AF: 0.480 AC: 21458 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 18382 AN: 26090

East Asian (EAS) AF: 0.368 AC: 14598 AN: 39676

South Asian (SAS) AF: 0.539 AC: 46406 AN: 86060

European-Finnish (FIN) AF: 0.720 AC: 38379 AN: 53298

Middle Eastern (MID) AF: 0.570 AC: 2734 AN: 4796

European-Non Finnish (NFE) AF: 0.729 AC: 805697 AN: 1104762

Other (OTH) AF: 0.653 AC: 39193 AN: 60056

GnomAD4 genome AF: 0.573 AC: 87149 AN: 151980 Hom.: 27839 Cov.: 32 AF XY: 0.569 AC XY: 42249 AN XY: 74314

African (AFR) AF: 0.296 AC: 12232 AN: 41394

American (AMR) AF: 0.562 AC: 8574 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.704 AC: 2440 AN: 3466

East Asian (EAS) AF: 0.373 AC: 1926 AN: 5168

South Asian (SAS) AF: 0.522 AC: 2516 AN: 4822

European-Finnish (FIN) AF: 0.707 AC: 7483 AN: 10582

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.734 AC: 49887 AN: 67966

Other (OTH) AF: 0.594 AC: 1255 AN: 2112

Alfa AF: 0.651 Hom.: 27745

Bravo AF: 0.547

Asia WGS AF: 0.465 AC: 1621 AN: 3478

EpiCase AF: 0.730

EpiControl AF: 0.724

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Freeman-Sheldon syndrome (2)
-	-	1	Arthrogryposis, distal, type 2B3 (1)
-	-	1	Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A (1)
-	-	1	Contractures, pterygia, and variable skeletal fusions syndrome 1B (1)
-	-	1	Distal arthrogryposis type 2B1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.3
DANN	Benign	0.44
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs876657; hg19: chr17-10544416; COSMIC: COSV56862462;