rs73976871

Variant names:

• chr17-10631783-C-A
• rs73976871
• NM_002470.4:c.5160+30G>T

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.5160+30G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0378 in 1,614,006 control chromosomes in the GnomAD database, including 1,398 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (140 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1258 hom.)
• Consequence: MYH3 NM_002470.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.723
• Publications: 3 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=-0.8).
• BP6: Variant 17-10631783-C-A is Benign according to our data. Variant chr17-10631783-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4	c.5160+30G>T		intron_variant	Intron 35 of 40	ENST00000583535.6	NP_002461.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.5160+30G>T		intron_variant	Intron 35 of 40	5	NM_002470.4	ENSP00000464317.1
MYHAS	ENST00000579914.2	n.705+17906C>A		intron_variant	Intron 4 of 4	4
MYHAS	ENST00000584139.2	n.1041+17906C>A		intron_variant	Intron 7 of 8	3
MYHAS	ENST00000781814.1	n.165-2902C>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0391 AC: 5941 AN: 151998 Hom.: 140 Cov.: 32

Gnomad AFR AF: 0.0612

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0192

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.00831

Gnomad SAS AF: 0.0696

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0349

Gnomad OTH AF: 0.0327

GnomAD2 exomes AF: 0.0331 AC: 8334 AN: 251432 AF XY: 0.0343

Gnomad AFR exome AF: 0.0578

Gnomad AMR exome AF: 0.0125

Gnomad ASJ exome AF: 0.0233

Gnomad EAS exome AF: 0.0103

Gnomad FIN exome AF: 0.0162

Gnomad NFE exome AF: 0.0349

Gnomad OTH exome AF: 0.0305

GnomAD4 exome AF: 0.0377 AC: 55123 AN: 1461890 Hom.: 1258 Cov.: 32 AF XY: 0.0380 AC XY: 27599 AN XY: 727244

African (AFR) AF: 0.0651 AC: 2179 AN: 33480

American (AMR) AF: 0.0124 AC: 555 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0235 AC: 613 AN: 26136

East Asian (EAS) AF: 0.00945 AC: 375 AN: 39700

South Asian (SAS) AF: 0.0653 AC: 5631 AN: 86256

European-Finnish (FIN) AF: 0.0172 AC: 917 AN: 53420

Middle Eastern (MID) AF: 0.0322 AC: 186 AN: 5768

European-Non Finnish (NFE) AF: 0.0381 AC: 42341 AN: 1112010

Other (OTH) AF: 0.0385 AC: 2326 AN: 60396

GnomAD4 genome AF: 0.0391 AC: 5945 AN: 152116 Hom.: 140 Cov.: 32 AF XY: 0.0383 AC XY: 2848 AN XY: 74366

African (AFR) AF: 0.0612 AC: 2537 AN: 41478

American (AMR) AF: 0.0192 AC: 293 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0277 AC: 96 AN: 3470

East Asian (EAS) AF: 0.00833 AC: 43 AN: 5164

South Asian (SAS) AF: 0.0699 AC: 337 AN: 4822

European-Finnish (FIN) AF: 0.0136 AC: 144 AN: 10600

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0349 AC: 2371 AN: 67984

Other (OTH) AF: 0.0328 AC: 69 AN: 2104

Alfa AF: 0.0341 Hom.: 16

Bravo AF: 0.0391

Asia WGS AF: 0.0350 AC: 120 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 26, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.099
DANN	Benign	0.73
PhyloP100		-0.72
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: rs73976871; hg19: chr17-10535100;