rs397750512

Positions:

• chr17-10630278-C-CT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002470.4(MYH3):​c.5457+9_5457+10insA 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

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.

• BP6: Variant 17-10630278-C-CT is Benign according to our data. Variant chr17-10630278-C-CT is described in ClinVar as [Likely_benign]. Clinvar id 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/exons	MANE	Protein	UniProt
MYH3	NM_002470.4	c.5457+9_5457+10insA		intron_variant		ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.5457+9_5457+10insA		intron_variant			XP_011522172.1
MYH3	XM_011523871.3	c.5457+9_5457+10insA		intron_variant			XP_011522173.1
MYH3	XM_047436127.1	c.5457+9_5457+10insA		intron_variant			XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.5457+9_5457+10insA		intron_variant		5	NM_002470.4	ENSP00000464317	P1

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

GnomAD3 exomes AF: 0.647 AC: 162805 AN: 251468 Hom.: 54778 AF XY: 0.655 AC XY: 88966 AN XY: 135900

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 SAS exome AF: 0.552

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

Gnomad4 AFR exome AF: 0.278

Gnomad4 AMR exome AF: 0.602

Gnomad4 ASJ exome AF: 0.713

Gnomad4 EAS exome AF: 0.526

Gnomad4 SAS exome AF: 0.552

Gnomad4 FIN exome AF: 0.751

Gnomad4 NFE exome AF: 0.733

Gnomad4 OTH exome AF: 0.666

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

Gnomad4 AFR AF: 0.297

Gnomad4 AMR AF: 0.620

Gnomad4 ASJ AF: 0.711

Gnomad4 EAS AF: 0.522

Gnomad4 SAS AF: 0.536

Gnomad4 FIN AF: 0.741

Gnomad4 NFE AF: 0.739

Gnomad4 OTH AF: 0.604

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

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 26, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Freeman-Sheldon syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 27, 2021	- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Arthrogryposis, distal, type 2B3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Arthrogryposis multiplex congenita Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs397750512; hg19: chr17-10533595;