17-10632032-C-G

Variant names:

• chr17-10632032-C-G
• rs2239936
• NM_002470.4:c.4957-16G>C

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.4957-16G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.791 in 1,611,690 control chromosomes in the GnomAD database, including 506,914 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (45994 hom., cov: 34)
  • Exomes 𝑓: 0.79 (460920 hom.)
• Consequence: MYH3 NM_002470.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.88
• Publications: 16 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]

LOC124903927 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-10632032-C-G is Benign according to our data. Variant chr17-10632032-C-G is described in ClinVar as Benign. ClinVar VariationId is 258691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.813 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.4957-16G>C		intron	N/A	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.4957-16G>C		intron	N/A	ENSP00000464317.1	P11055
	MYH3	ENST00000961194.1		c.4957-16G>C		intron	N/A	ENSP00000631253.1
	MYHAS	ENST00000579914.2	TSL:4	n.705+18155C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.775 AC: 117851 AN: 152050 Hom.: 45962 Cov.: 34

Gnomad AFR AF: 0.765

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.708

Gnomad ASJ AF: 0.764

Gnomad EAS AF: 0.538

Gnomad SAS AF: 0.716

Gnomad FIN AF: 0.786

Gnomad MID AF: 0.678

Gnomad NFE AF: 0.819

Gnomad OTH AF: 0.747

GnomAD2 exomes AF: 0.752 AC: 186624 AN: 248234 AF XY: 0.756

Gnomad AFR exome AF: 0.773

Gnomad AMR exome AF: 0.651

Gnomad ASJ exome AF: 0.769

Gnomad EAS exome AF: 0.534

Gnomad FIN exome AF: 0.798

Gnomad NFE exome AF: 0.811

Gnomad OTH exome AF: 0.766

GnomAD4 exome AF: 0.793 AC: 1156688 AN: 1459522 Hom.: 460920 Cov.: 50 AF XY: 0.791 AC XY: 574330 AN XY: 726106

African (AFR) AF: 0.754 AC: 25218 AN: 33432

American (AMR) AF: 0.660 AC: 29436 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.768 AC: 20064 AN: 26130

East Asian (EAS) AF: 0.543 AC: 21551 AN: 39686

South Asian (SAS) AF: 0.723 AC: 62310 AN: 86162

European-Finnish (FIN) AF: 0.801 AC: 42299 AN: 52788

Middle Eastern (MID) AF: 0.680 AC: 3200 AN: 4708

European-Non Finnish (NFE) AF: 0.815 AC: 905999 AN: 1111736

Other (OTH) AF: 0.773 AC: 46611 AN: 60270

GnomAD4 genome AF: 0.775 AC: 117943 AN: 152168 Hom.: 45994 Cov.: 34 AF XY: 0.768 AC XY: 57116 AN XY: 74394

African (AFR) AF: 0.765 AC: 31733 AN: 41506

American (AMR) AF: 0.708 AC: 10832 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.764 AC: 2653 AN: 3472

East Asian (EAS) AF: 0.538 AC: 2767 AN: 5144

South Asian (SAS) AF: 0.716 AC: 3449 AN: 4820

European-Finnish (FIN) AF: 0.786 AC: 8331 AN: 10600

Middle Eastern (MID) AF: 0.682 AC: 199 AN: 292

European-Non Finnish (NFE) AF: 0.818 AC: 55675 AN: 68022

Other (OTH) AF: 0.750 AC: 1582 AN: 2108

Alfa AF: 0.770 Hom.: 5120

Bravo AF: 0.765

Asia WGS AF: 0.665 AC: 2316 AN: 3478

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	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	Freeman-Sheldon syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.27
DANN	Benign	0.36
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

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: rs2239936; hg19: chr17-10535349; COSMIC: COSV56866645; COSMIC: COSV56866645;