rs2285472

Variant names:

• chr17-10639569-T-C
• rs2285472
• NM_002470.4:c.2916A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-10639569-T-C
• chr17-10639569-T-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.2916A>G​(p.Thr972Thr) 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 1,613,792 control chromosomes in the GnomAD database, including 379,770 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (27813 hom., cov: 32)
  • Exomes 𝑓: 0.69 (351957 hom.)
• Consequence: MYH3 NM_002470.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -3.87
• Publications: 22 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=-0.61).
• BP6: Variant 17-10639569-T-C is Benign according to our data. Variant chr17-10639569-T-C is described in ClinVar as Benign. ClinVar VariationId is 129652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.87 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.728 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.2916A>G	p.Thr972Thr	synonymous	Exon 23 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.2916A>G	p.Thr972Thr	synonymous	Exon 23 of 41	ENSP00000464317.1	P11055
	MYH3	ENST00000961194.1		c.2916A>G	p.Thr972Thr	synonymous	Exon 22 of 40	ENSP00000631253.1
	MYHAS	ENST00000579914.2	TSL:4	n.705+25692T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.573 AC: 87065 AN: 151930 Hom.: 27807 Cov.: 32

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.743

Gnomad AMR AF: 0.561

Gnomad ASJ AF: 0.703

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.706

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.734

Gnomad OTH AF: 0.591

GnomAD2 exomes AF: 0.610 AC: 153454 AN: 251488 AF XY: 0.622

Gnomad AFR exome AF: 0.294

Gnomad AMR exome AF: 0.467

Gnomad ASJ exome AF: 0.708

Gnomad EAS exome AF: 0.362

Gnomad FIN exome AF: 0.714

Gnomad NFE exome AF: 0.728

Gnomad OTH exome AF: 0.653

GnomAD4 exome AF: 0.686 AC: 1002176 AN: 1461744 Hom.: 351957 Cov.: 74 AF XY: 0.684 AC XY: 497604 AN XY: 727168

African (AFR) AF: 0.277 AC: 9266 AN: 33480

American (AMR) AF: 0.480 AC: 21462 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 18414 AN: 26136

East Asian (EAS) AF: 0.368 AC: 14611 AN: 39700

South Asian (SAS) AF: 0.539 AC: 46515 AN: 86248

European-Finnish (FIN) AF: 0.720 AC: 38448 AN: 53420

Middle Eastern (MID) AF: 0.557 AC: 3188 AN: 5724

European-Non Finnish (NFE) AF: 0.729 AC: 810869 AN: 1111928

Other (OTH) AF: 0.653 AC: 39403 AN: 60384

GnomAD4 genome AF: 0.573 AC: 87097 AN: 152048 Hom.: 27813 Cov.: 32 AF XY: 0.568 AC XY: 42192 AN XY: 74304

African (AFR) AF: 0.295 AC: 12228 AN: 41488

American (AMR) AF: 0.561 AC: 8559 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.703 AC: 2441 AN: 3472

East Asian (EAS) AF: 0.373 AC: 1930 AN: 5178

South Asian (SAS) AF: 0.523 AC: 2518 AN: 4818

European-Finnish (FIN) AF: 0.706 AC: 7449 AN: 10544

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

European-Non Finnish (NFE) AF: 0.734 AC: 49877 AN: 67972

Other (OTH) AF: 0.595 AC: 1259 AN: 2116

Alfa AF: 0.662 Hom.: 26871

Bravo AF: 0.547

Asia WGS AF: 0.464 AC: 1620 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	-0.61
CADD	Benign	0.64
DANN	Benign	0.68
PhyloP100		-3.9
Mutation Taster		=85/15	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2285472; hg19: chr17-10542886; COSMIC: COSV56862439;