rs4792008

chr17-10632444-G-A

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.4956+32C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 1,604,222 control chromosomes in the GnomAD database, including 377,489 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (27810 hom., cov: 33)
  • Exomes 𝑓: 0.69 (349679 hom.)
• Consequence: MYH3 NM_002470.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0540

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]

LOC124903927 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-10632444-G-A is Benign according to our data. Variant chr17-10632444-G-A is described in ClinVar as [Benign]. Clinvar id is 258690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.728 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH3	NM_002470.4	c.4956+32C>T		intron_variant		ENST00000583535.6
LOC124903927	XR_007065620.1	n.221+680G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH3	ENST00000583535.6	c.4956+32C>T		intron_variant		5	NM_002470.4	P1

Frequencies

GnomAD3 genomes AF: 0.573 AC: 87100 AN: 152014 Hom.: 27808 Cov.: 33

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.743

Gnomad AMR AF: 0.561

Gnomad ASJ AF: 0.703

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.524

Gnomad FIN AF: 0.706

Gnomad MID AF: 0.548

Gnomad NFE AF: 0.733

Gnomad OTH AF: 0.589

GnomAD3 exomes AF: 0.607 AC: 148956 AN: 245230 Hom.: 48151 AF XY: 0.620 AC XY: 82597 AN XY: 133124

Gnomad AFR exome AF: 0.294

Gnomad AMR exome AF: 0.467

Gnomad ASJ exome AF: 0.707

Gnomad EAS exome AF: 0.362

Gnomad SAS exome AF: 0.540

Gnomad FIN exome AF: 0.714

Gnomad NFE exome AF: 0.727

Gnomad OTH exome AF: 0.652

GnomAD4 exome AF: 0.686 AC: 995503 AN: 1452090 Hom.: 349679 Cov.: 33 AF XY: 0.684 AC XY: 494676 AN XY: 722910

Gnomad4 AFR exome AF: 0.277

Gnomad4 AMR exome AF: 0.479

Gnomad4 ASJ exome AF: 0.704

Gnomad4 EAS exome AF: 0.367

Gnomad4 SAS exome AF: 0.540

Gnomad4 FIN exome AF: 0.719

Gnomad4 NFE exome AF: 0.729

Gnomad4 OTH exome AF: 0.652

GnomAD4 genome AF: 0.573 AC: 87125 AN: 152132 Hom.: 27810 Cov.: 33 AF XY: 0.568 AC XY: 42234 AN XY: 74356

Gnomad4 AFR AF: 0.295

Gnomad4 AMR AF: 0.561

Gnomad4 ASJ AF: 0.703

Gnomad4 EAS AF: 0.371

Gnomad4 SAS AF: 0.523

Gnomad4 FIN AF: 0.706

Gnomad4 NFE AF: 0.733

Gnomad4 OTH AF: 0.589

Alfa AF: 0.655 Hom.: 12553

Bravo AF: 0.547

Asia WGS AF: 0.448 AC: 1564 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

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

- -

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	-0.82
Cadd	Benign	1.8
Dann	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs4792008; hg19: chr17-10535761; COSMIC: COSV56865868; COSMIC: COSV56865868;