rs61735358

Variant names:

• chr17-10638180-C-T
• rs61735358
• NM_002470.4:c.3592G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002470.4(MYH3):​c.3592G>A​(p.Ala1198Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00831 in 1,613,956 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1198V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0062 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0085 (70 hom.)
• Consequence: MYH3 NM_002470.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 4.97

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013158917).
• BP6: Variant 17-10638180-C-T is Benign according to our data. Variant chr17-10638180-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 211552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10638180-C-T is described in Lovd as [Benign]. Variant chr17-10638180-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00625 (950/152072) while in subpopulation NFE AF = 0.0104 (704/68004). AF 95% confidence interval is 0.00972. There are 6 homozygotes in GnomAd4. There are 433 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 950 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH3	NM_002470.4	c.3592G>A	p.Ala1198Thr	missense_variant	Exon 27 of 41	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.3592G>A	p.Ala1198Thr	missense_variant	Exon 27 of 41		XP_011522172.1
MYH3	XM_011523871.3	c.3592G>A	p.Ala1198Thr	missense_variant	Exon 27 of 41		XP_011522173.1
MYH3	XM_047436127.1	c.3592G>A	p.Ala1198Thr	missense_variant	Exon 29 of 43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.3592G>A	p.Ala1198Thr	missense_variant	Exon 27 of 41	5	NM_002470.4	ENSP00000464317.1

Frequencies

GnomAD3 genomes AF: 0.00625 AC: 950 AN: 151954 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00617

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00530

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00637 AC: 1603 AN: 251480 AF XY: 0.00627

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00312

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00702

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.00635

GnomAD4 exome AF: 0.00852 AC: 12460 AN: 1461884 Hom.: 70 Cov.: 31 AF XY: 0.00820 AC XY: 5965 AN XY: 727246

Gnomad4 AFR exome AF: 0.00152 AC: 51 AN: 33480

Gnomad4 AMR exome AF: 0.00318 AC: 142 AN: 44724

Gnomad4 ASJ exome AF: 0.000459 AC: 12 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.00151 AC: 130 AN: 86258

Gnomad4 FIN exome AF: 0.00749 AC: 400 AN: 53414

Gnomad4 NFE exome AF: 0.0101 AC: 11228 AN: 1112008

Gnomad4 Remaining exome AF: 0.00742 AC: 448 AN: 60396

GnomAD4 genome AF: 0.00625 AC: 950 AN: 152072 Hom.: 6 Cov.: 31 AF XY: 0.00583 AC XY: 433 AN XY: 74324

Gnomad4 AFR AF: 0.00164 AC: 0.00163871 AN: 0.00163871

Gnomad4 AMR AF: 0.00616 AC: 0.00615747 AN: 0.00615747

Gnomad4 ASJ AF: 0.00144 AC: 0.00144259 AN: 0.00144259

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00125 AC: 0.00125052 AN: 0.00125052

Gnomad4 FIN AF: 0.00530 AC: 0.00529701 AN: 0.00529701

Gnomad4 NFE AF: 0.0104 AC: 0.0103523 AN: 0.0103523

Gnomad4 OTH AF: 0.00521 AC: 0.00520833 AN: 0.00520833

Alfa AF: 0.00863 Hom.: 8

Bravo AF: 0.00593

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0105 AC: 90

ExAC AF: 0.00676 AC: 821

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00987

EpiControl AF: 0.0105

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYH3: BS1, BS2 -

Dec 23, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 27, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:4

Aug 04, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Freeman-Sheldon syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	0.052
Eigen_PC	Benign	0.099
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.50	T
Sift4G	Benign	0.31	T
Polyphen		0.089	B
Vest4		0.19
MVP		0.68
MPC		0.39
ClinPred		0.026	T
GERP RS		5.5
Varity_R		0.11
gMVP		0.19
Mutation Taster		=91/9	polymorphism

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: rs61735358; hg19: chr17-10541497;