rs112569418

Variant names:

• chr17-10635411-G-A
• rs112569418
• NM_002470.4:c.4128C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-10635411-G-A
• chr17-10635411-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002470.4(MYH3):​c.4128C>T​(p.Tyr1376Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00721 in 1,614,022 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (38 hom., cov: 33)
  • Exomes 𝑓: 0.0064 (79 hom.)
• Consequence: MYH3 NM_002470.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.37
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-10635411-G-A is Benign according to our data. Variant chr17-10635411-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.37 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0151 (2293/152330) while in subpopulation AFR AF = 0.0399 (1660/41560). AF 95% confidence interval is 0.0383. There are 38 homozygotes in GnomAd4. There are 1076 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 AD,AR gene

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.4128C>T	p.Tyr1376Tyr	synonymous	Exon 30 of 41	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.4128C>T	p.Tyr1376Tyr	synonymous	Exon 30 of 41	ENSP00000464317.1	P11055
	MYH3	ENST00000961194.1		c.4128C>T	p.Tyr1376Tyr	synonymous	Exon 29 of 40	ENSP00000631253.1
	MYHAS	ENST00000579914.2	TSL:4	n.705+21534G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2279 AN: 152212 Hom.: 37 Cov.: 33

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00942

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00531

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00804 AC: 2021 AN: 251276 AF XY: 0.00794

Gnomad AFR exome AF: 0.0400

Gnomad AMR exome AF: 0.00601

Gnomad ASJ exome AF: 0.0171

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00590

Gnomad OTH exome AF: 0.00685

GnomAD4 exome AF: 0.00639 AC: 9343 AN: 1461692 Hom.: 79 Cov.: 32 AF XY: 0.00640 AC XY: 4652 AN XY: 727156

African (AFR) AF: 0.0419 AC: 1401 AN: 33472

American (AMR) AF: 0.00651 AC: 291 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0178 AC: 466 AN: 26134

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.00879 AC: 758 AN: 86250

European-Finnish (FIN) AF: 0.00129 AC: 69 AN: 53420

Middle Eastern (MID) AF: 0.0206 AC: 119 AN: 5764

European-Non Finnish (NFE) AF: 0.00512 AC: 5696 AN: 1111856

Other (OTH) AF: 0.00893 AC: 539 AN: 60380

GnomAD4 genome AF: 0.0151 AC: 2293 AN: 152330 Hom.: 38 Cov.: 33 AF XY: 0.0144 AC XY: 1076 AN XY: 74496

African (AFR) AF: 0.0399 AC: 1660 AN: 41560

American (AMR) AF: 0.00934 AC: 143 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00808 AC: 39 AN: 4828

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10620

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00532 AC: 362 AN: 68032

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.00963 Hom.: 3

Bravo AF: 0.0169

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.00709

EpiControl AF: 0.00658

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Distal arthrogryposis type 2B1 (1)
-	-	1	Freeman-Sheldon syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.1
DANN	Benign	0.88
PhyloP100		-1.4
Mutation Taster		=98/2	polymorphism

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: rs112569418; hg19: chr17-10538728; COSMIC: COSV56869697;