17-10639602-G-T

Variant names:

• chr17-10639602-G-T
• rs144338240
• NM_002470.4:c.2883C>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_002470.4(MYH3):​c.2883C>A​(p.Thr961Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,613,932 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00097 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: MYH3 NM_002470.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.91
• Publications: 0 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 17-10639602-G-T is Benign according to our data. Variant chr17-10639602-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.91 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.2883C>A	p.Thr961Thr	synonymous	Exon 23 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.2883C>A	p.Thr961Thr	synonymous	Exon 23 of 41	ENSP00000464317.1	P11055
	MYH3	ENST00000961194.1		c.2883C>A	p.Thr961Thr	synonymous	Exon 22 of 40	ENSP00000631253.1
	MYHAS	ENST00000579914.2	TSL:4	n.705+25725G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000961 AC: 146 AN: 151952 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00243

Gnomad ASJ AF: 0.000578

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.000961

GnomAD2 exomes AF: 0.00108 AC: 272 AN: 251494 AF XY: 0.00107

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00149

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00112 AC: 1632 AN: 1461862 Hom.: 3 Cov.: 60 AF XY: 0.00113 AC XY: 822 AN XY: 727236

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.00181 AC: 81 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000880 AC: 23 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000336 AC: 29 AN: 86254

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53418

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5754

European-Non Finnish (NFE) AF: 0.00126 AC: 1406 AN: 1112006

Other (OTH) AF: 0.00121 AC: 73 AN: 60394

GnomAD4 genome AF: 0.000967 AC: 147 AN: 152070 Hom.: 1 Cov.: 31 AF XY: 0.000888 AC XY: 66 AN XY: 74336

African (AFR) AF: 0.000193 AC: 8 AN: 41502

American (AMR) AF: 0.00243 AC: 37 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.000578 AC: 2 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4804

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10576

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

European-Non Finnish (NFE) AF: 0.00141 AC: 96 AN: 67990

Other (OTH) AF: 0.000951 AC: 2 AN: 2104

Alfa AF: 0.00133 Hom.: 0

Bravo AF: 0.00122

EpiCase AF: 0.00169

EpiControl AF: 0.00225

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	-0.78
CADD	Benign	0.087
DANN	Benign	0.61
PhyloP100		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs144338240; hg19: chr17-10542919; COSMIC: COSV56862907;