rs2239933

Variant names:

• chr17-10645867-G-A
• rs2239933
• NM_002470.4:c.1003-22C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-10645867-G-A
• chr17-10645867-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002470.4(MYH3):​c.1003-22C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.674 in 1,613,298 control chromosomes in the GnomAD database, including 379,272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (27745 hom., cov: 30)
  • Exomes 𝑓: 0.68 (351527 hom.)
• Consequence: MYH3 NM_002470.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.444
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-10645867-G-A is Benign according to our data. Variant chr17-10645867-G-A is described in ClinVar as Benign. ClinVar VariationId is 258667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.1003-22C>T		intron	N/A	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.1003-22C>T		intron	N/A	ENSP00000464317.1	P11055
	MYH3	ENST00000961194.1		c.1003-22C>T		intron	N/A	ENSP00000631253.1
	MYHAS	ENST00000579914.2	TSL:4	n.705+31990G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.573 AC: 86825 AN: 151556 Hom.: 27738 Cov.: 30

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.743

Gnomad AMR AF: 0.561

Gnomad ASJ AF: 0.702

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.522

Gnomad FIN AF: 0.708

Gnomad MID AF: 0.545

Gnomad NFE AF: 0.734

Gnomad OTH AF: 0.591

GnomAD2 exomes AF: 0.609 AC: 152995 AN: 251284 AF XY: 0.621

Gnomad AFR exome AF: 0.292

Gnomad AMR exome AF: 0.466

Gnomad ASJ exome AF: 0.706

Gnomad EAS exome AF: 0.349

Gnomad FIN exome AF: 0.715

Gnomad NFE exome AF: 0.728

Gnomad OTH exome AF: 0.651

GnomAD4 exome AF: 0.685 AC: 1000977 AN: 1461624 Hom.: 351527 Cov.: 61 AF XY: 0.684 AC XY: 497057 AN XY: 727124

African (AFR) AF: 0.276 AC: 9241 AN: 33470

American (AMR) AF: 0.479 AC: 21428 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.704 AC: 18389 AN: 26136

East Asian (EAS) AF: 0.345 AC: 13677 AN: 39694

South Asian (SAS) AF: 0.539 AC: 46499 AN: 86250

European-Finnish (FIN) AF: 0.720 AC: 38462 AN: 53410

Middle Eastern (MID) AF: 0.556 AC: 3207 AN: 5768

European-Non Finnish (NFE) AF: 0.729 AC: 810760 AN: 1111784

Other (OTH) AF: 0.651 AC: 39314 AN: 60388

GnomAD4 genome AF: 0.573 AC: 86857 AN: 151674 Hom.: 27745 Cov.: 30 AF XY: 0.568 AC XY: 42067 AN XY: 74088

African (AFR) AF: 0.294 AC: 12168 AN: 41328

American (AMR) AF: 0.561 AC: 8539 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 2436 AN: 3470

East Asian (EAS) AF: 0.360 AC: 1823 AN: 5070

South Asian (SAS) AF: 0.521 AC: 2505 AN: 4806

European-Finnish (FIN) AF: 0.708 AC: 7433 AN: 10506

Middle Eastern (MID) AF: 0.541 AC: 158 AN: 292

European-Non Finnish (NFE) AF: 0.734 AC: 49860 AN: 67946

Other (OTH) AF: 0.595 AC: 1257 AN: 2114

Alfa AF: 0.639 Hom.: 6952

Bravo AF: 0.546

Asia WGS AF: 0.460 AC: 1605 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (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	Freeman-Sheldon syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.65
DANN	Benign	0.51
PhyloP100		-0.44
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2239933;

hg19: chr17-10549184;

COSMIC: COSV56861483;

COSMIC: COSV56861483;