rs201626

Variant names:

• chr17-10638424-A-G
• rs201626
• NM_002470.4:c.3348T>C

Variant summary

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

The NM_002470.4(MYH3):​c.3348T>C​(p.Ile1116Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,599,252 control chromosomes in the GnomAD database, including 20,966 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2539 hom., cov: 30)
  • Exomes 𝑓: 0.12 (18427 hom.)
• Consequence: MYH3 NM_002470.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.54
• Publications: 13 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=-0.83).
• BP6: Variant 17-10638424-A-G is Benign according to our data. Variant chr17-10638424-A-G is described in ClinVar as Benign. ClinVar VariationId is 129657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.54 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.586 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.3348T>C	p.Ile1116Ile	synonymous	Exon 27 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.3348T>C	p.Ile1116Ile	synonymous	Exon 27 of 41	ENSP00000464317.1	P11055
	MYH3	ENST00000961194.1		c.3348T>C	p.Ile1116Ile	synonymous	Exon 26 of 40	ENSP00000631253.1
	MYHAS	ENST00000579914.2	TSL:4	n.705+24547A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22686 AN: 151524 Hom.: 2547 Cov.: 30

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.0912

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.605

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.0874

Gnomad OTH AF: 0.169

GnomAD2 exomes AF: 0.199 AC: 47042 AN: 236198 AF XY: 0.190

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.364

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.614

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.0917

Gnomad OTH exome AF: 0.171

GnomAD4 exome AF: 0.122 AC: 176203 AN: 1447612 Hom.: 18427 Cov.: 38 AF XY: 0.124 AC XY: 89293 AN XY: 720532

African (AFR) AF: 0.152 AC: 5077 AN: 33472

American (AMR) AF: 0.350 AC: 15649 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 4382 AN: 26136

East Asian (EAS) AF: 0.602 AC: 23903 AN: 39682

South Asian (SAS) AF: 0.231 AC: 19955 AN: 86224

European-Finnish (FIN) AF: 0.131 AC: 5158 AN: 39500

Middle Eastern (MID) AF: 0.161 AC: 927 AN: 5758

European-Non Finnish (NFE) AF: 0.0829 AC: 92166 AN: 1111876

Other (OTH) AF: 0.149 AC: 8986 AN: 60304

GnomAD4 genome AF: 0.150 AC: 22694 AN: 151640 Hom.: 2539 Cov.: 30 AF XY: 0.159 AC XY: 11754 AN XY: 74054

African (AFR) AF: 0.147 AC: 6093 AN: 41348

American (AMR) AF: 0.251 AC: 3816 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 638 AN: 3466

East Asian (EAS) AF: 0.604 AC: 3069 AN: 5080

South Asian (SAS) AF: 0.246 AC: 1177 AN: 4790

European-Finnish (FIN) AF: 0.141 AC: 1479 AN: 10512

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.0875 AC: 5940 AN: 67924

Other (OTH) AF: 0.167 AC: 351 AN: 2104

Alfa AF: 0.120 Hom.: 4382

Bravo AF: 0.163

Asia WGS AF: 0.373 AC: 1292 AN: 3478

EpiCase AF: 0.0951

EpiControl AF: 0.101

ClinVar

ClinVar submissions

Significance: 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	-0.83
CADD	Benign	1.3
DANN	Benign	0.51
PhyloP100		-1.5
Mutation Taster		=97/3	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: rs201626; hg19: chr17-10541741; COSMIC: COSV56860805;