rs12941197

Variant names:

• chr17-10638363-G-A
• rs12941197
• NM_002470.4:c.3409C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1137H) has been classified as Uncertain significance.

• 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
• Publications: 11 publications found

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]

MYHAS (HGNC:50609): (myosin heavy chain gene cluster antisense RNA) Predicted to enable primary miRNA binding activity. Predicted to be involved in response to muscle activity and skeletal muscle fiber development. Predicted to act upstream of or within with a positive effect on gene expression. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• 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 Benign/Likely_benign. ClinVar VariationId is 258680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002470.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	NM_002470.4	MANE Select	c.3409C>T	p.Arg1137Cys	missense	Exon 27 of 41	NP_002461.2	P11055

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH3	ENST00000583535.6	TSL:5 MANE Select	c.3409C>T	p.Arg1137Cys	missense	Exon 27 of 41	ENSP00000464317.1	P11055
	MYH3	ENST00000961194.1		c.3409C>T	p.Arg1137Cys	missense	Exon 26 of 40	ENSP00000631253.1
	MYHAS	ENST00000579914.2	TSL:4	n.705+24486G>A		intron	N/A

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

GnomAD2 exomes AF: 0.00256 AC: 631 AN: 246366 AF XY: 0.00264

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 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

African (AFR) AF: 0.000478 AC: 16 AN: 33480

American (AMR) AF: 0.000537 AC: 24 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00170 AC: 147 AN: 86256

European-Finnish (FIN) AF: 0.00227 AC: 108 AN: 47502

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.00447 AC: 4967 AN: 1111966

Other (OTH) AF: 0.00242 AC: 146 AN: 60352

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

African (AFR) AF: 0.000675 AC: 28 AN: 41492

American (AMR) AF: 0.000524 AC: 8 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5136

South Asian (SAS) AF: 0.00167 AC: 8 AN: 4804

European-Finnish (FIN) AF: 0.00227 AC: 24 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00422 AC: 287 AN: 68002

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.00340 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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Distal arthrogryposis type 2B1 (1)
-	-	1	Freeman-Sheldon syndrome (1)
-	-	1	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 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.2
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
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

Other links and lift over

dbSNP: rs12941197; hg19: chr17-10541680;