chr17-10640068-T-C

Variant names:

• chr17-10640068-T-C
• rs56163389
• NM_002470.4:c.2610A>G

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.2610A>G​(p.Lys870Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0415 in 1,614,096 control chromosomes in the GnomAD database, including 1,895 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (401 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1494 hom.)
• Consequence: MYH3 NM_002470.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.978
• 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=-0.71).
• BP6: Variant 17-10640068-T-C is Benign according to our data. Variant chr17-10640068-T-C is described in ClinVar as Benign. ClinVar VariationId is 129651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.978 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 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.2610A>G	p.Lys870Lys	synonymous	Exon 22 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.2610A>G	p.Lys870Lys	synonymous	Exon 22 of 41	ENSP00000464317.1	P11055
	MYH3	ENST00000961194.1		c.2610A>G	p.Lys870Lys	synonymous	Exon 21 of 40	ENSP00000631253.1
	MYHAS	ENST00000579914.2	TSL:4	n.705+26191T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0583 AC: 8870 AN: 152098 Hom.: 401 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0276

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.00886

Gnomad SAS AF: 0.0699

Gnomad FIN AF: 0.0138

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0355

Gnomad OTH AF: 0.0431

GnomAD2 exomes AF: 0.0388 AC: 9757 AN: 251492 AF XY: 0.0383

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.0180

Gnomad ASJ exome AF: 0.0240

Gnomad EAS exome AF: 0.0105

Gnomad FIN exome AF: 0.0161

Gnomad NFE exome AF: 0.0352

Gnomad OTH exome AF: 0.0354

GnomAD4 exome AF: 0.0398 AC: 58140 AN: 1461880 Hom.: 1494 Cov.: 70 AF XY: 0.0397 AC XY: 28865 AN XY: 727242

African (AFR) AF: 0.132 AC: 4426 AN: 33480

American (AMR) AF: 0.0183 AC: 820 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0246 AC: 644 AN: 26136

East Asian (EAS) AF: 0.00952 AC: 378 AN: 39700

South Asian (SAS) AF: 0.0650 AC: 5609 AN: 86254

European-Finnish (FIN) AF: 0.0171 AC: 916 AN: 53420

Middle Eastern (MID) AF: 0.0382 AC: 220 AN: 5760

European-Non Finnish (NFE) AF: 0.0382 AC: 42532 AN: 1112010

Other (OTH) AF: 0.0430 AC: 2595 AN: 60396

GnomAD4 genome AF: 0.0583 AC: 8873 AN: 152216 Hom.: 401 Cov.: 32 AF XY: 0.0563 AC XY: 4194 AN XY: 74438

African (AFR) AF: 0.127 AC: 5261 AN: 41494

American (AMR) AF: 0.0276 AC: 422 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 101 AN: 3472

East Asian (EAS) AF: 0.00888 AC: 46 AN: 5180

South Asian (SAS) AF: 0.0702 AC: 338 AN: 4814

European-Finnish (FIN) AF: 0.0138 AC: 146 AN: 10614

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0354 AC: 2411 AN: 68020

Other (OTH) AF: 0.0431 AC: 91 AN: 2112

Alfa AF: 0.0451 Hom.: 120

Bravo AF: 0.0602

Asia WGS AF: 0.0390 AC: 134 AN: 3478

EpiCase AF: 0.0317

EpiControl AF: 0.0331

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	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	-0.71
CADD	Benign	3.1
DANN	Benign	0.63
PhyloP100		-0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs56163389; hg19: chr17-10543385;