rs2285466

Variant names:

• chr17-10651711-G-A
• rs2285466
• NM_002470.4:c.349-43C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-10651711-G-A
• chr17-10651711-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.349-43C>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 1,601,802 control chromosomes in the GnomAD database, including 376,596 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (27436 hom., cov: 27)
  • Exomes 𝑓: 0.68 (349160 hom.)
• Consequence: MYH3 NM_002470.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.21
• Publications: 6 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=-0.89).
• BP6: Variant 17-10651711-G-A is Benign according to our data. Variant chr17-10651711-G-A is described in ClinVar as Benign. ClinVar VariationId is 258682.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4	c.349-43C>T		intron_variant	Intron 4 of 40	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.349-43C>T		intron_variant	Intron 4 of 40		XP_011522172.1
MYH3	XM_011523871.3	c.349-43C>T		intron_variant	Intron 4 of 40		XP_011522173.1
MYH3	XM_047436127.1	c.349-43C>T		intron_variant	Intron 6 of 42		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.349-43C>T		intron_variant	Intron 4 of 40	5	NM_002470.4	ENSP00000464317.1
MYH3	ENST00000579489.2	n.258C>T		non_coding_transcript_exon_variant	Exon 1 of 4	5
MYHAS	ENST00000579914.2	n.706-32224G>A		intron_variant	Intron 4 of 4	4
MYHAS	ENST00000584139.2	n.1042-29022G>A		intron_variant	Intron 7 of 8	3

Frequencies

GnomAD3 genomes AF: 0.572 AC: 85801 AN: 150070 Hom.: 27433 Cov.: 27

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.746

Gnomad AMR AF: 0.560

Gnomad ASJ AF: 0.702

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.522

Gnomad FIN AF: 0.702

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.734

Gnomad OTH AF: 0.591

GnomAD2 exomes AF: 0.608 AC: 152221 AN: 250196 AF XY: 0.621

Gnomad AFR exome AF: 0.292

Gnomad AMR exome AF: 0.467

Gnomad ASJ exome AF: 0.706

Gnomad EAS exome AF: 0.349

Gnomad FIN exome AF: 0.714

Gnomad NFE exome AF: 0.727

Gnomad OTH exome AF: 0.651

GnomAD4 exome AF: 0.685 AC: 994213 AN: 1451630 Hom.: 349160 Cov.: 36 AF XY: 0.684 AC XY: 494131 AN XY: 722812

African (AFR) AF: 0.277 AC: 9167 AN: 33152

American (AMR) AF: 0.479 AC: 21400 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.704 AC: 18329 AN: 26036

East Asian (EAS) AF: 0.344 AC: 13612 AN: 39606

South Asian (SAS) AF: 0.539 AC: 46374 AN: 86016

European-Finnish (FIN) AF: 0.720 AC: 38349 AN: 53280

Middle Eastern (MID) AF: 0.556 AC: 3190 AN: 5736

European-Non Finnish (NFE) AF: 0.729 AC: 804707 AN: 1103152

Other (OTH) AF: 0.651 AC: 39085 AN: 60020

GnomAD4 genome AF: 0.572 AC: 85824 AN: 150172 Hom.: 27436 Cov.: 27 AF XY: 0.566 AC XY: 41329 AN XY: 73066

African (AFR) AF: 0.291 AC: 11896 AN: 40814

American (AMR) AF: 0.560 AC: 8435 AN: 15072

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 2431 AN: 3464

East Asian (EAS) AF: 0.356 AC: 1806 AN: 5066

South Asian (SAS) AF: 0.521 AC: 2486 AN: 4772

European-Finnish (FIN) AF: 0.702 AC: 6961 AN: 9910

Middle Eastern (MID) AF: 0.548 AC: 160 AN: 292

European-Non Finnish (NFE) AF: 0.734 AC: 49734 AN: 67792

Other (OTH) AF: 0.595 AC: 1238 AN: 2082

Alfa AF: 0.645 Hom.: 6151

Bravo AF: 0.546

Asia WGS AF: 0.460 AC: 1603 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

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

- -

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 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	-0.89
CADD	Benign	0.23
DANN	Benign	0.46
PhyloP100		-1.2
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: rs2285466; hg19: chr17-10555028; COSMIC: COSV56864835; COSMIC: COSV56864835;