rs1989810

Positions:

• chr17-10649729-A-G
• chr17-10649729-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002470.4(MYH3):​c.534-44T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.716 in 1,580,702 control chromosomes in the GnomAD database, including 415,084 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.63 (32090 hom., cov: 32)
  • Exomes 𝑓: 0.72 (382994 hom.)
• Consequence: MYH3 NM_002470.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.434

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]

MYH3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This place is a probable branch point but rather VUS (scored 5 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-10649729-A-G is Benign according to our data. Variant chr17-10649729-A-G is described in ClinVar as [Benign]. Clinvar id is 258695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH3	NM_002470.4	c.534-44T>C		intron_variant		ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.534-44T>C		intron_variant			XP_011522172.1
MYH3	XM_011523871.3	c.534-44T>C		intron_variant			XP_011522173.1
MYH3	XM_047436127.1	c.534-44T>C		intron_variant			XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.534-44T>C		intron_variant		5	NM_002470.4	ENSP00000464317.1
MYH3	ENST00000579489.2	n.486-44T>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.630 AC: 95764 AN: 151914 Hom.: 32081 Cov.: 32

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.588

Gnomad ASJ AF: 0.732

Gnomad EAS AF: 0.367

Gnomad SAS AF: 0.592

Gnomad FIN AF: 0.721

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.769

Gnomad OTH AF: 0.635

GnomAD3 exomes AF: 0.648 AC: 162616 AN: 251048 Hom.: 55356 AF XY: 0.660 AC XY: 89519 AN XY: 135730

Gnomad AFR exome AF: 0.419

Gnomad AMR exome AF: 0.485

Gnomad ASJ exome AF: 0.730

Gnomad EAS exome AF: 0.360

Gnomad SAS exome AF: 0.605

Gnomad FIN exome AF: 0.731

Gnomad NFE exome AF: 0.763

Gnomad OTH exome AF: 0.687

GnomAD4 exome AF: 0.725 AC: 1035758 AN: 1428670 Hom.: 382994 Cov.: 24 AF XY: 0.723 AC XY: 515946 AN XY: 713150

Gnomad4 AFR exome AF: 0.408

Gnomad4 AMR exome AF: 0.497

Gnomad4 ASJ exome AF: 0.729

Gnomad4 EAS exome AF: 0.355

Gnomad4 SAS exome AF: 0.605

Gnomad4 FIN exome AF: 0.737

Gnomad4 NFE exome AF: 0.769

Gnomad4 OTH exome AF: 0.695

GnomAD4 genome AF: 0.630 AC: 95798 AN: 152032 Hom.: 32090 Cov.: 32 AF XY: 0.623 AC XY: 46328 AN XY: 74314

Gnomad4 AFR AF: 0.419

Gnomad4 AMR AF: 0.589

Gnomad4 ASJ AF: 0.732

Gnomad4 EAS AF: 0.368

Gnomad4 SAS AF: 0.592

Gnomad4 FIN AF: 0.721

Gnomad4 NFE AF: 0.769

Gnomad4 OTH AF: 0.639

Alfa AF: 0.709 Hom.: 10847

Bravo AF: 0.606

Asia WGS AF: 0.499 AC: 1739 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Freeman-Sheldon syndrome 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

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

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

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.0
DANN	Benign	0.26
BranchPoint Hunter		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1989810; hg19: chr17-10553046; COSMIC: COSV56862486; COSMIC: COSV56862486;