rs147148934

Positions:

• chr17-10648602-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_002470.4(MYH3):​c.690C>G​(p.Ala230=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00495 in 1,613,692 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (38 hom.)
• Consequence: MYH3 NM_002470.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.44

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 17-10648602-G-C is Benign according to our data. Variant chr17-10648602-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 258703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10648602-G-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.44 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00501 (7319/1461434) while in subpopulation MID AF= 0.0163 (94/5762). AF 95% confidence interval is 0.0136. There are 38 homozygotes in gnomad4_exome. There are 3723 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 665 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH3	NM_002470.4	c.690C>G	p.Ala230=	synonymous_variant	8/41	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.690C>G	p.Ala230=	synonymous_variant	8/41		XP_011522172.1
MYH3	XM_011523871.3	c.690C>G	p.Ala230=	synonymous_variant	8/41		XP_011522173.1
MYH3	XM_047436127.1	c.690C>G	p.Ala230=	synonymous_variant	10/43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.690C>G	p.Ala230=	synonymous_variant	8/41	5	NM_002470.4	ENSP00000464317	P1
MYH3	ENST00000579489.2			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00436 AC: 664 AN: 152140 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00642

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00510

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00504 AC: 1267 AN: 251492 Hom.: 7 AF XY: 0.00567 AC XY: 771 AN XY: 135920

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00338

Gnomad ASJ exome AF: 0.0171

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00800

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.00572

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00501 AC: 7319 AN: 1461434 Hom.: 38 Cov.: 31 AF XY: 0.00512 AC XY: 3723 AN XY: 727036

Gnomad4 AFR exome AF: 0.00188

Gnomad4 AMR exome AF: 0.00356

Gnomad4 ASJ exome AF: 0.0176

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00850

Gnomad4 FIN exome AF: 0.00129

Gnomad4 NFE exome AF: 0.00486

Gnomad4 OTH exome AF: 0.00563

GnomAD4 genome AF: 0.00437 AC: 665 AN: 152258 Hom.: 2 Cov.: 32 AF XY: 0.00435 AC XY: 324 AN XY: 74460

Gnomad4 AFR AF: 0.00245

Gnomad4 AMR AF: 0.00641

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00809

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00512

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00691 Hom.: 4

Bravo AF: 0.00491

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00692

EpiControl AF: 0.00622

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	MYH3: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

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	-0.46
CADD	Benign	13
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs147148934; hg19: chr17-10551919;