chr17-10655059-A-G

Variant names:

• chr17-10655059-A-G
• rs17817203
• NM_002470.4:c.6T>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.6T>C​(p.Ser2Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0204 in 1,613,930 control chromosomes in the GnomAD database, including 359 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (35 hom., cov: 32)
  • Exomes 𝑓: 0.020 (324 hom.)
• Consequence: MYH3 NM_002470.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.02
• Publications: 5 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=-0.68).
• BP6: Variant 17-10655059-A-G is Benign according to our data. Variant chr17-10655059-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.02 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.022 (3348/152132) while in subpopulation AFR AF = 0.031 (1285/41492). AF 95% confidence interval is 0.0296. There are 35 homozygotes in GnomAd4. There are 1604 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 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.6T>C	p.Ser2Ser	synonymous	Exon 3 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.6T>C	p.Ser2Ser	synonymous	Exon 3 of 41	ENSP00000464317.1	P11055
	MYH3	ENST00000961194.1		c.6T>C	p.Ser2Ser	synonymous	Exon 2 of 40	ENSP00000631253.1
	MYH3	ENST00000582580.1	TSL:5	n.94T>C		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3343 AN: 152014 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.0310

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0138

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.0270

Gnomad FIN AF: 0.0191

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0212

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0180 AC: 4537 AN: 251470 AF XY: 0.0187

Gnomad AFR exome AF: 0.0298

Gnomad AMR exome AF: 0.00781

Gnomad ASJ exome AF: 0.00873

Gnomad EAS exome AF: 0.000870

Gnomad FIN exome AF: 0.0175

Gnomad NFE exome AF: 0.0201

Gnomad OTH exome AF: 0.0184

GnomAD4 exome AF: 0.0202 AC: 29530 AN: 1461798 Hom.: 324 Cov.: 33 AF XY: 0.0205 AC XY: 14875 AN XY: 727206

African (AFR) AF: 0.0290 AC: 972 AN: 33474

American (AMR) AF: 0.00780 AC: 349 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00838 AC: 219 AN: 26136

East Asian (EAS) AF: 0.00589 AC: 234 AN: 39700

South Asian (SAS) AF: 0.0289 AC: 2489 AN: 86256

European-Finnish (FIN) AF: 0.0165 AC: 883 AN: 53418

Middle Eastern (MID) AF: 0.00765 AC: 44 AN: 5750

European-Non Finnish (NFE) AF: 0.0209 AC: 23198 AN: 1111946

Other (OTH) AF: 0.0189 AC: 1142 AN: 60394

GnomAD4 genome AF: 0.0220 AC: 3348 AN: 152132 Hom.: 35 Cov.: 32 AF XY: 0.0216 AC XY: 1604 AN XY: 74362

African (AFR) AF: 0.0310 AC: 1285 AN: 41492

American (AMR) AF: 0.0137 AC: 210 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.00252 AC: 13 AN: 5166

South Asian (SAS) AF: 0.0272 AC: 131 AN: 4818

European-Finnish (FIN) AF: 0.0191 AC: 202 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0212 AC: 1440 AN: 68010

Other (OTH) AF: 0.0213 AC: 45 AN: 2112

Alfa AF: 0.0201 Hom.: 65

Bravo AF: 0.0211

Asia WGS AF: 0.0360 AC: 125 AN: 3478

EpiCase AF: 0.0208

EpiControl AF: 0.0181

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	-0.68
CADD	Benign	0.79
DANN	Benign	0.51
PhyloP100		-1.0
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: rs17817203; hg19: chr17-10558376; COSMIC: COSV56870734; COSMIC: COSV56870734;