rs1989810

Variant names:

• chr17-10649729-A-G
• rs1989810
• NM_002470.4:c.534-44T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-10649729-A-G
• chr17-10649729-A-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.534-44T>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 1,580,702 control chromosomes in the GnomAD database, including 415,084 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.63 (32090 hom., cov: 32)
  • Exomes 𝑓: 0.72 (382994 hom.)
• Consequence: MYH3 NM_002470.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.434
• Publications: 7 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: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 5 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-10649729-A-G is Benign according to our data. Variant chr17-10649729-A-G is described in ClinVar as Benign. ClinVar VariationId is 258695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4	c.534-44T>C		intron_variant	Intron 6 of 40	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.534-44T>C		intron_variant	Intron 6 of 40		XP_011522172.1
MYH3	XM_011523871.3	c.534-44T>C		intron_variant	Intron 6 of 40		XP_011522173.1
MYH3	XM_047436127.1	c.534-44T>C		intron_variant	Intron 8 of 42		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.534-44T>C		intron_variant	Intron 6 of 40	5	NM_002470.4	ENSP00000464317.1
MYH3	ENST00000579489.2	n.486-44T>C		intron_variant	Intron 2 of 3	5
MYHAS	ENST00000579914.2	n.706-34206A>G		intron_variant	Intron 4 of 4	4
MYHAS	ENST00000584139.2	n.1042-31004A>G		intron_variant	Intron 7 of 8	3

Frequencies

GnomAD3 genomes AF: 0.630 AC: 95764 AN: 151914 Hom.: 32081 Cov.: 32

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.588

Gnomad ASJ AF: 0.732

Gnomad EAS AF: 0.367

Gnomad SAS AF: 0.592

Gnomad FIN AF: 0.721

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.769

Gnomad OTH AF: 0.635

GnomAD2 exomes AF: 0.648 AC: 162616 AN: 251048 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: 0.360

Gnomad FIN exome AF: 0.731

Gnomad NFE exome AF: 0.763

Gnomad OTH exome AF: 0.687

GnomAD4 exome AF: 0.725 AC: 1035758 AN: 1428670 Hom.: 382994 Cov.: 24 AF XY: 0.723 AC XY: 515946 AN XY: 713150

African (AFR) AF: 0.408 AC: 13309 AN: 32594

American (AMR) AF: 0.497 AC: 22226 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.729 AC: 18873 AN: 25900

East Asian (EAS) AF: 0.355 AC: 14010 AN: 39486

South Asian (SAS) AF: 0.605 AC: 51755 AN: 85494

European-Finnish (FIN) AF: 0.737 AC: 39275 AN: 53266

Middle Eastern (MID) AF: 0.593 AC: 3378 AN: 5696

European-Non Finnish (NFE) AF: 0.769 AC: 831758 AN: 1082288

Other (OTH) AF: 0.695 AC: 41174 AN: 59270

GnomAD4 genome AF: 0.630 AC: 95798 AN: 152032 Hom.: 32090 Cov.: 32 AF XY: 0.623 AC XY: 46328 AN XY: 74314

African (AFR) AF: 0.419 AC: 17367 AN: 41440

American (AMR) AF: 0.589 AC: 8987 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.732 AC: 2537 AN: 3468

East Asian (EAS) AF: 0.368 AC: 1897 AN: 5154

South Asian (SAS) AF: 0.592 AC: 2856 AN: 4822

European-Finnish (FIN) AF: 0.721 AC: 7630 AN: 10576

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

European-Non Finnish (NFE) AF: 0.769 AC: 52284 AN: 67992

Other (OTH) AF: 0.639 AC: 1345 AN: 2104

Alfa AF: 0.708 Hom.: 16466

Bravo AF: 0.606

Asia WGS AF: 0.499 AC: 1739 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Freeman-Sheldon syndrome Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arthrogryposis, distal, type 2B3 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Contractures, pterygia, and variable skeletal fusions syndrome 1B Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.0
DANN	Benign	0.26
PhyloP100		0.43
BranchPoint Hunter		5.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1989810; hg19: chr17-10553046; COSMIC: COSV56862486; COSMIC: COSV56862486;