rs188588330

Variant names:

• chr17-10639482-G-A
• rs188588330
• NM_002470.4:c.2926-8C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-10639482-G-A
• chr17-10639482-G-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002470.4(MYH3):​c.2926-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,614,004 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (7 hom.)
• Consequence: MYH3 NM_002470.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006412
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.48
• 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]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 17-10639482-G-A is Benign according to our data. Variant chr17-10639482-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 258677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4	c.2926-8C>T		splice_region_variant, intron_variant	Intron 23 of 40	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.2926-8C>T		splice_region_variant, intron_variant	Intron 23 of 40		XP_011522172.1
MYH3	XM_011523871.3	c.2926-8C>T		splice_region_variant, intron_variant	Intron 23 of 40		XP_011522173.1
MYH3	XM_047436127.1	c.2926-8C>T		splice_region_variant, intron_variant	Intron 25 of 42		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.2926-8C>T		splice_region_variant, intron_variant	Intron 23 of 40	5	NM_002470.4	ENSP00000464317.1
MYHAS	ENST00000579914.2	n.705+25605G>A		intron_variant	Intron 4 of 4	4
MYHAS	ENST00000584139.2	n.1041+25605G>A		intron_variant	Intron 7 of 8	3

Frequencies

GnomAD3 genomes AF: 0.00280 AC: 426 AN: 152096 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00622

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00412

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00275 AC: 691 AN: 251384 AF XY: 0.00289

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00494

Gnomad NFE exome AF: 0.00405

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00311 AC: 4549 AN: 1461790 Hom.: 7 Cov.: 68 AF XY: 0.00314 AC XY: 2286 AN XY: 727200

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.00233 AC: 104 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000497 AC: 13 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86252

European-Finnish (FIN) AF: 0.00504 AC: 269 AN: 53418

Middle Eastern (MID) AF: 0.00505 AC: 29 AN: 5744

European-Non Finnish (NFE) AF: 0.00353 AC: 3922 AN: 1111956

Other (OTH) AF: 0.00268 AC: 162 AN: 60386

GnomAD4 genome AF: 0.00280 AC: 426 AN: 152214 Hom.: 3 Cov.: 33 AF XY: 0.00291 AC XY: 217 AN XY: 74446

African (AFR) AF: 0.000433 AC: 18 AN: 41536

American (AMR) AF: 0.00190 AC: 29 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00622 AC: 66 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00412 AC: 280 AN: 68012

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00357 Hom.: 1

Bravo AF: 0.00249

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYH3: BP4 -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

MYH3-related disorder Benign:1

Jun 24, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Freeman-Sheldon syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Distal arthrogryposis type 2B1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	9.5
DANN	Benign	0.57
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000064
dbscSNV1_RF	Benign	0.0040
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: rs188588330; hg19: chr17-10542799;