17-10639482-G-A

Position:

• chr17-10639482-G-A

Variant summary

Our verdict is Benign. Variant got -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, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00006412
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.48

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]

ACMG classification

Verdict is Benign. Variant got -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. Variant chr17-10639482-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 426 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH3	NM_002470.4	c.2926-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.2926-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_011522172.1
MYH3	XM_011523871.3	c.2926-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_011522173.1
MYH3	XM_047436127.1	c.2926-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.2926-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_002470.4	ENSP00000464317	P1

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

GnomAD3 exomes AF: 0.00275 AC: 691 AN: 251384 Hom.: 0 AF XY: 0.00289 AC XY: 393 AN XY: 135902

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 SAS exome AF: 0.000229

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

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00233

Gnomad4 ASJ exome AF: 0.000497

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000406

Gnomad4 FIN exome AF: 0.00504

Gnomad4 NFE exome AF: 0.00353

Gnomad4 OTH exome AF: 0.00268

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

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00622

Gnomad4 NFE AF: 0.00412

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00403 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

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	MYH3: BP4 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

MYH3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 24, 2019

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs188588330; hg19: chr17-10542799;