rs150348272

Positions:

• chr17-10634829-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002470.4(MYH3):​c.4356+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00532 in 1,614,052 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (43 hom.)
• Consequence: MYH3 NM_002470.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.38

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=-0.9).
• BP6: Variant 17-10634829-G-A is Benign according to our data. Variant chr17-10634829-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 258684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00534 (7801/1461858) while in subpopulation MID AF= 0.0191 (110/5768). AF 95% confidence interval is 0.0162. There are 43 homozygotes in gnomad4_exome. There are 3962 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 780 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH3	NM_002470.4	c.4356+11C>T		intron_variant		ENST00000583535.6
LOC124903927	XR_007065620.1	n.366G>A		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH3	ENST00000583535.6	c.4356+11C>T		intron_variant		5	NM_002470.4	P1

Frequencies

GnomAD3 genomes AF: 0.00512 AC: 779 AN: 152074 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00471

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00708

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00810

Gnomad FIN AF: 0.000850

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.00525

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00531 AC: 1334 AN: 251422 Hom.: 7 AF XY: 0.00591 AC XY: 803 AN XY: 135904

Gnomad AFR exome AF: 0.00345

Gnomad AMR exome AF: 0.00393

Gnomad ASJ exome AF: 0.0171

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00810

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00583

Gnomad OTH exome AF: 0.00521

GnomAD4 exome AF: 0.00534 AC: 7801 AN: 1461858 Hom.: 43 Cov.: 32 AF XY: 0.00545 AC XY: 3962 AN XY: 727230

Gnomad4 AFR exome AF: 0.00490

Gnomad4 AMR exome AF: 0.00407

Gnomad4 ASJ exome AF: 0.0178

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00873

Gnomad4 FIN exome AF: 0.00129

Gnomad4 NFE exome AF: 0.00511

Gnomad4 OTH exome AF: 0.00618

GnomAD4 genome AF: 0.00513 AC: 780 AN: 152194 Hom.: 2 Cov.: 33 AF XY: 0.00493 AC XY: 367 AN XY: 74406

Gnomad4 AFR AF: 0.00474

Gnomad4 AMR AF: 0.00707

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00790

Gnomad4 FIN AF: 0.000850

Gnomad4 NFE AF: 0.00526

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00733 Hom.: 1

Bravo AF: 0.00585

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 24, 2020	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

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	-0.90
CADD	Benign	0.014
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150348272; hg19: chr17-10538146;