chr17-10642813-T-G

Variant names:

• chr17-10642813-T-G
• rs2285468
• NM_002470.4:c.1581+13A>C

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.1581+13A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.716 in 1,613,388 control chromosomes in the GnomAD database, including 423,631 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (32086 hom., cov: 31)
  • Exomes 𝑓: 0.72 (391545 hom.)
• Consequence: MYH3 NM_002470.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.895
• Publications: 12 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=-0.9).
• BP6: Variant 17-10642813-T-G is Benign according to our data. Variant chr17-10642813-T-G is described in ClinVar as Benign. ClinVar VariationId is 258671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.764 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.1581+13A>C		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.1581+13A>C		intron	N/A	ENSP00000464317.1	P11055
	MYH3	ENST00000961194.1		c.1581+13A>C		intron	N/A	ENSP00000631253.1
	MYHAS	ENST00000579914.2	TSL:4	n.705+28936T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.632 AC: 95718 AN: 151540 Hom.: 32078 Cov.: 31

Gnomad AFR AF: 0.421

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.590

Gnomad ASJ AF: 0.731

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.592

Gnomad FIN AF: 0.723

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.769

Gnomad OTH AF: 0.633

GnomAD2 exomes AF: 0.648 AC: 162880 AN: 251420 AF XY: 0.660

Gnomad AFR exome AF: 0.419

Gnomad AMR exome AF: 0.485

Gnomad ASJ exome AF: 0.730

Gnomad EAS exome AF: 0.361

Gnomad FIN exome AF: 0.731

Gnomad NFE exome AF: 0.763

Gnomad OTH exome AF: 0.687

GnomAD4 exome AF: 0.725 AC: 1059165 AN: 1461730 Hom.: 391545 Cov.: 120 AF XY: 0.723 AC XY: 525940 AN XY: 727168

African (AFR) AF: 0.405 AC: 13566 AN: 33470

American (AMR) AF: 0.498 AC: 22255 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.728 AC: 19032 AN: 26132

East Asian (EAS) AF: 0.355 AC: 14074 AN: 39696

South Asian (SAS) AF: 0.604 AC: 52111 AN: 86254

European-Finnish (FIN) AF: 0.737 AC: 39384 AN: 53420

Middle Eastern (MID) AF: 0.594 AC: 3428 AN: 5768

European-Non Finnish (NFE) AF: 0.768 AC: 853419 AN: 1111904

Other (OTH) AF: 0.694 AC: 41896 AN: 60374

GnomAD4 genome AF: 0.631 AC: 95751 AN: 151658 Hom.: 32086 Cov.: 31 AF XY: 0.625 AC XY: 46292 AN XY: 74106

African (AFR) AF: 0.421 AC: 17333 AN: 41218

American (AMR) AF: 0.590 AC: 8982 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.731 AC: 2539 AN: 3472

East Asian (EAS) AF: 0.371 AC: 1897 AN: 5108

South Asian (SAS) AF: 0.592 AC: 2843 AN: 4804

European-Finnish (FIN) AF: 0.723 AC: 7641 AN: 10568

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.769 AC: 52284 AN: 67950

Other (OTH) AF: 0.637 AC: 1337 AN: 2098

Alfa AF: 0.706 Hom.: 100397

Bravo AF: 0.606

Asia WGS AF: 0.500 AC: 1742 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	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	-0.90
CADD	Benign	0.12
DANN	Benign	0.34
PhyloP100		-0.90
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2285468; hg19: chr17-10546130; COSMIC: COSV56868340;