rs2285479

Variant names:

• chr17-10632701-G-A
• rs2285479
• NM_002470.4:c.4731C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000583535.6(MYH3):​c.4731C>T​(p.Ile1577Ile) 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 1,613,692 control chromosomes in the GnomAD database, including 379,821 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (27894 hom., cov: 32)
  • Exomes 𝑓: 0.69 (351927 hom.)
• Consequence: MYH3 ENST00000583535.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -4.90
• Publications: 21 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]

LOC124903927 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 17-10632701-G-A is Benign according to our data. Variant chr17-10632701-G-A is described in ClinVar as Benign. ClinVar VariationId is 129663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.9 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: ENST00000583535.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	NM_002470.4	MANE Select	c.4731C>T	p.Ile1577Ile	synonymous	Exon 34 of 41	NP_002461.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	ENST00000583535.6	TSL:5 MANE Select	c.4731C>T	p.Ile1577Ile	synonymous	Exon 34 of 41	ENSP00000464317.1
	MYHAS	ENST00000579914.2	TSL:4	n.705+18824G>A		intron	N/A
	MYHAS	ENST00000584139.2	TSL:3	n.1041+18824G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.575 AC: 87312 AN: 151846 Hom.: 27892 Cov.: 32

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.746

Gnomad AMR AF: 0.562

Gnomad ASJ AF: 0.703

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.707

Gnomad MID AF: 0.548

Gnomad NFE AF: 0.733

Gnomad OTH AF: 0.591

GnomAD2 exomes AF: 0.611 AC: 153517 AN: 251450 AF XY: 0.623

Gnomad AFR exome AF: 0.299

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: 0.727

Gnomad OTH exome AF: 0.652

GnomAD4 exome AF: 0.686 AC: 1002231 AN: 1461728 Hom.: 351927 Cov.: 55 AF XY: 0.684 AC XY: 497622 AN XY: 727170

African (AFR) AF: 0.282 AC: 9456 AN: 33480

American (AMR) AF: 0.480 AC: 21468 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 18418 AN: 26136

East Asian (EAS) AF: 0.367 AC: 14576 AN: 39698

South Asian (SAS) AF: 0.540 AC: 46599 AN: 86254

European-Finnish (FIN) AF: 0.720 AC: 38426 AN: 53404

Middle Eastern (MID) AF: 0.559 AC: 3223 AN: 5768

European-Non Finnish (NFE) AF: 0.729 AC: 810672 AN: 1111870

Other (OTH) AF: 0.652 AC: 39393 AN: 60394

GnomAD4 genome AF: 0.575 AC: 87339 AN: 151964 Hom.: 27894 Cov.: 32 AF XY: 0.570 AC XY: 42322 AN XY: 74270

African (AFR) AF: 0.301 AC: 12473 AN: 41406

American (AMR) AF: 0.562 AC: 8585 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.703 AC: 2440 AN: 3470

East Asian (EAS) AF: 0.371 AC: 1918 AN: 5166

South Asian (SAS) AF: 0.523 AC: 2517 AN: 4812

European-Finnish (FIN) AF: 0.707 AC: 7465 AN: 10560

Middle Eastern (MID) AF: 0.545 AC: 159 AN: 292

European-Non Finnish (NFE) AF: 0.733 AC: 49859 AN: 67976

Other (OTH) AF: 0.591 AC: 1246 AN: 2110

Alfa AF: 0.674 Hom.: 55847

Bravo AF: 0.549

Asia WGS AF: 0.449 AC: 1567 AN: 3478

EpiCase AF: 0.729

EpiControl AF: 0.723

ClinVar

ClinVar submissions as Germline

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	-0.77
CADD	Benign	0.034
DANN	Benign	0.53
PhyloP100		-4.9
Mutation Taster		=99/1	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: rs2285479; hg19: chr17-10536018; COSMIC: COSV56862393; COSMIC: COSV56862393;