chr17-10640701-T-C

Variant names:

• chr17-10640701-T-C
• rs876660
• NM_002470.4:c.2166-15A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002470.4(MYH3):​c.2166-15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 1,612,398 control chromosomes in the GnomAD database, including 379,611 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (27853 hom., cov: 33)
  • Exomes 𝑓: 0.69 (351758 hom.)
• Consequence: MYH3 NM_002470.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.939
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 17-10640701-T-C is Benign according to our data. Variant chr17-10640701-T-C is described in ClinVar as Benign. ClinVar VariationId is 258673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.728 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.2166-15A>G		intron	N/A	NP_002461.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	ENST00000583535.6	TSL:5 MANE Select	c.2166-15A>G		intron	N/A	ENSP00000464317.1
	MYH3	ENST00000961194.1		c.2166-15A>G		intron	N/A	ENSP00000631253.1
	MYHAS	ENST00000579914.2	TSL:4	n.705+26824T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.573 AC: 87151 AN: 152028 Hom.: 27847 Cov.: 33

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.743

Gnomad AMR AF: 0.561

Gnomad ASJ AF: 0.703

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.707

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.734

Gnomad OTH AF: 0.591

GnomAD2 exomes AF: 0.610 AC: 152331 AN: 249632 AF XY: 0.622

Gnomad AFR exome AF: 0.294

Gnomad AMR exome AF: 0.468

Gnomad ASJ exome AF: 0.708

Gnomad EAS exome AF: 0.362

Gnomad FIN exome AF: 0.715

Gnomad NFE exome AF: 0.728

Gnomad OTH exome AF: 0.653

GnomAD4 exome AF: 0.686 AC: 1001402 AN: 1460252 Hom.: 351758 Cov.: 49 AF XY: 0.684 AC XY: 497236 AN XY: 726468

African (AFR) AF: 0.277 AC: 9243 AN: 33428

American (AMR) AF: 0.480 AC: 21419 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 18408 AN: 26122

East Asian (EAS) AF: 0.368 AC: 14601 AN: 39682

South Asian (SAS) AF: 0.539 AC: 46492 AN: 86200

European-Finnish (FIN) AF: 0.720 AC: 38351 AN: 53250

Middle Eastern (MID) AF: 0.559 AC: 3188 AN: 5702

European-Non Finnish (NFE) AF: 0.729 AC: 810347 AN: 1110962

Other (OTH) AF: 0.653 AC: 39353 AN: 60308

GnomAD4 genome AF: 0.573 AC: 87183 AN: 152146 Hom.: 27853 Cov.: 33 AF XY: 0.568 AC XY: 42273 AN XY: 74396

African (AFR) AF: 0.295 AC: 12243 AN: 41502

American (AMR) AF: 0.561 AC: 8564 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.703 AC: 2441 AN: 3470

East Asian (EAS) AF: 0.373 AC: 1926 AN: 5170

South Asian (SAS) AF: 0.523 AC: 2522 AN: 4824

European-Finnish (FIN) AF: 0.707 AC: 7501 AN: 10608

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.734 AC: 49891 AN: 67992

Other (OTH) AF: 0.595 AC: 1257 AN: 2112

Alfa AF: 0.654 Hom.: 11945

Bravo AF: 0.547

Asia WGS AF: 0.464 AC: 1620 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Freeman-Sheldon syndrome (2)
-	-	1	Arthrogryposis, distal, type 2B3 (1)
-	-	1	Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A (1)
-	-	1	Contractures, pterygia, and variable skeletal fusions syndrome 1B (1)
-	-	1	Distal arthrogryposis type 2B1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.14
DANN	Benign	0.45
PhyloP100		-0.94
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs876660; hg19: chr17-10544018; COSMIC: COSV56863448;