rs397750512

Variant names:

• chr17-10630278-C-CT
• rs397750512
• NM_002470.4:c.5457+9dupA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002470.4(MYH3):​c.5457+9dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.689 in 1,613,880 control chromosomes in the GnomAD database, including 392,432 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (29258 hom., cov: 0)
  • Exomes 𝑓: 0.70 (363174 hom.)
• Consequence: MYH3 NM_002470.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.63
• Publications: 2 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.

• BP6: Variant 17-10630278-C-CT is Benign according to our data. Variant chr17-10630278-C-CT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.733 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4	c.5457+9dupA		intron_variant	Intron 37 of 40	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.5457+9dupA		intron_variant	Intron 37 of 40		XP_011522172.1
MYH3	XM_011523871.3	c.5457+9dupA		intron_variant	Intron 37 of 40		XP_011522173.1
MYH3	XM_047436127.1	c.5457+9dupA		intron_variant	Intron 39 of 42		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.5457+9_5457+10insA		intron_variant	Intron 37 of 40	5	NM_002470.4	ENSP00000464317.1

Frequencies

GnomAD3 genomes AF: 0.590 AC: 89619 AN: 151876 Hom.: 29259 Cov.: 0

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.743

Gnomad AMR AF: 0.619

Gnomad ASJ AF: 0.711

Gnomad EAS AF: 0.522

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.741

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.739

Gnomad OTH AF: 0.604

GnomAD2 exomes AF: 0.647 AC: 162805 AN: 251468 AF XY: 0.655

Gnomad AFR exome AF: 0.295

Gnomad AMR exome AF: 0.595

Gnomad ASJ exome AF: 0.715

Gnomad EAS exome AF: 0.520

Gnomad FIN exome AF: 0.747

Gnomad NFE exome AF: 0.733

Gnomad OTH exome AF: 0.677

GnomAD4 exome AF: 0.699 AC: 1021853 AN: 1461886 Hom.: 363174 Cov.: 35 AF XY: 0.697 AC XY: 507033 AN XY: 727240

African (AFR) AF: 0.278 AC: 9298 AN: 33480

American (AMR) AF: 0.602 AC: 26902 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.713 AC: 18643 AN: 26136

East Asian (EAS) AF: 0.526 AC: 20896 AN: 39700

South Asian (SAS) AF: 0.552 AC: 47645 AN: 86258

European-Finnish (FIN) AF: 0.751 AC: 40104 AN: 53420

Middle Eastern (MID) AF: 0.561 AC: 3238 AN: 5768

European-Non Finnish (NFE) AF: 0.733 AC: 814898 AN: 1112004

Other (OTH) AF: 0.666 AC: 40229 AN: 60396

GnomAD4 genome AF: 0.590 AC: 89638 AN: 151994 Hom.: 29258 Cov.: 0 AF XY: 0.588 AC XY: 43678 AN XY: 74310

African (AFR) AF: 0.297 AC: 12296 AN: 41434

American (AMR) AF: 0.620 AC: 9465 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.711 AC: 2467 AN: 3470

East Asian (EAS) AF: 0.522 AC: 2685 AN: 5142

South Asian (SAS) AF: 0.536 AC: 2587 AN: 4826

European-Finnish (FIN) AF: 0.741 AC: 7827 AN: 10568

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.739 AC: 50199 AN: 67962

Other (OTH) AF: 0.604 AC: 1274 AN: 2110

Alfa AF: 0.680 Hom.: 8115

Bravo AF: 0.567

Asia WGS AF: 0.513 AC: 1790 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 26, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Freeman-Sheldon syndrome Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Contractures, pterygia, and variable skeletal fusions syndrome 1B Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arthrogryposis, distal, type 2B3 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arthrogryposis multiplex congenita Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs397750512; hg19: chr17-10533595;