17-10633757-G-A

Variant names:

• chr17-10633757-G-A
• rs73976873
• NM_002470.4:c.4523-42C>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.4523-42C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00399 in 1,612,094 control chromosomes in the GnomAD database, including 173 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (94 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (79 hom.)
• Consequence: MYH3 NM_002470.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.60
• 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]

LOC124903927 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 17-10633757-G-A is Benign according to our data. Variant chr17-10633757-G-A is described in ClinVar as Benign. ClinVar VariationId is 258686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0657 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	NM_002470.4	MANE Select	c.4523-42C>T		intron	N/A	NP_002461.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	ENST00000583535.6	TSL:5 MANE Select	c.4523-42C>T		intron	N/A	ENSP00000464317.1
	MYHAS	ENST00000579914.2	TSL:4	n.705+19880G>A		intron	N/A
	MYHAS	ENST00000584139.2	TSL:3	n.1041+19880G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0200 AC: 3037 AN: 152228 Hom.: 94 Cov.: 33

Gnomad AFR AF: 0.0680

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00909

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00601 AC: 1502 AN: 249998 AF XY: 0.00430

Gnomad AFR exome AF: 0.0730

Gnomad AMR exome AF: 0.00581

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000146

Gnomad NFE exome AF: 0.000652

Gnomad OTH exome AF: 0.00458

GnomAD4 exome AF: 0.00232 AC: 3390 AN: 1459748 Hom.: 79 Cov.: 32 AF XY: 0.00198 AC XY: 1438 AN XY: 726312

African (AFR) AF: 0.0696 AC: 2328 AN: 33458

American (AMR) AF: 0.00635 AC: 284 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 32 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86246

European-Finnish (FIN) AF: 0.000290 AC: 15 AN: 51638

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5768

European-Non Finnish (NFE) AF: 0.000358 AC: 398 AN: 1111718

Other (OTH) AF: 0.00474 AC: 286 AN: 60370

GnomAD4 genome AF: 0.0199 AC: 3036 AN: 152346 Hom.: 94 Cov.: 33 AF XY: 0.0188 AC XY: 1398 AN XY: 74516

African (AFR) AF: 0.0678 AC: 2818 AN: 41562

American (AMR) AF: 0.00908 AC: 139 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68036

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.00816 Hom.: 9

Bravo AF: 0.0222

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Apr 03, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0020
DANN	Benign	0.61
PhyloP100		-2.6
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: rs73976873; hg19: chr17-10537074; COSMIC: COSV56864084; COSMIC: COSV56864084;