rs12941197

Positions:

• chr17-10638363-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_002470.4(MYH3):​c.3409C>T​(p.Arg1137Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,607,938 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0037 (15 hom.)
• Consequence: MYH3 NM_002470.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.23

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 -15 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH3. . Gene score misZ 1.7445 (greater than the threshold 3.09). Trascript score misZ 4.649 (greater than threshold 3.09). GenCC has associacion of gene with spondylocarpotarsal synostosis syndrome, contractures, pterygia, and variable skeletal fusions syndrome 1B, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, digitotalar dysmorphism, autosomal recessive multiple pterygium syndrome, Freeman-Sheldon syndrome, distal arthrogryposis type 2B1, Sheldon-hall syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.014895111).
• BP6: Variant 17-10638363-G-A is Benign according to our data. Variant chr17-10638363-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 258680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10638363-G-A is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 359 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH3	NM_002470.4	c.3409C>T	p.Arg1137Cys	missense_variant	27/41	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.3409C>T	p.Arg1137Cys	missense_variant	27/41		XP_011522172.1
MYH3	XM_011523871.3	c.3409C>T	p.Arg1137Cys	missense_variant	27/41		XP_011522173.1
MYH3	XM_047436127.1	c.3409C>T	p.Arg1137Cys	missense_variant	29/43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.3409C>T	p.Arg1137Cys	missense_variant	27/41	5	NM_002470.4	ENSP00000464317.1

Frequencies

GnomAD3 genomes AF: 0.00236 AC: 359 AN: 151944 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000677

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00227

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00422

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00256 AC: 631 AN: 246366 Hom.: 3 AF XY: 0.00264 AC XY: 353 AN XY: 133680

Gnomad AFR exome AF: 0.000560

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00147

Gnomad FIN exome AF: 0.00219

Gnomad NFE exome AF: 0.00450

Gnomad OTH exome AF: 0.00247

GnomAD4 exome AF: 0.00372 AC: 5415 AN: 1455876 Hom.: 15 Cov.: 38 AF XY: 0.00371 AC XY: 2688 AN XY: 724536

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00170

Gnomad4 FIN exome AF: 0.00227

Gnomad4 NFE exome AF: 0.00447

Gnomad4 OTH exome AF: 0.00242

GnomAD4 genome AF: 0.00236 AC: 359 AN: 152062 Hom.: 2 Cov.: 31 AF XY: 0.00226 AC XY: 168 AN XY: 74306

Gnomad4 AFR AF: 0.000675

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00167

Gnomad4 FIN AF: 0.00227

Gnomad4 NFE AF: 0.00422

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00347 Hom.: 1

Bravo AF: 0.00193

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00294 AC: 357

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00379

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	MYH3: BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Freeman-Sheldon syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 03, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Freeman-Sheldon syndrome;C1867440:Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A;C5193098:Arthrogryposis, distal, type 2B3;C5193114:Contractures, pterygia, and variable skeletal fusions syndrome 1B Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 26, 2021

- -

Distal arthrogryposis type 2B1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 03, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.015	T
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	4.3	H
PrimateAI	Uncertain	0.56	T
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.32
MVP		0.90
MPC		0.34
ClinPred		0.076	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.53

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: rs12941197; hg19: chr17-10541680;