rs1555525941

Positions:

• chr17-10638943-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The NM_002470.4(MYH3):​c.3269A>C​(p.Gln1090Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH3 NM_002470.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.21

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 26 curated benign missense variants. GenCC has associacion of the 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.
• PP5: Variant 17-10638943-T-G is Pathogenic according to our data. Variant chr17-10638943-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521706.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH3	NM_002470.4	c.3269A>C	p.Gln1090Pro	missense_variant	26/41	ENST00000583535.6	NP_002461.2
MYH3	XM_011523870.4	c.3269A>C	p.Gln1090Pro	missense_variant	26/41		XP_011522172.1
MYH3	XM_011523871.3	c.3269A>C	p.Gln1090Pro	missense_variant	26/41		XP_011522173.1
MYH3	XM_047436127.1	c.3269A>C	p.Gln1090Pro	missense_variant	28/43		XP_047292083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH3	ENST00000583535.6	c.3269A>C	p.Gln1090Pro	missense_variant	26/41	5	NM_002470.4	ENSP00000464317.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 24, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Uncertain	0.63	T
Sift4G	Uncertain	0.038	D
Polyphen		0.86	P
Vest4		0.51
MutPred		0.64		Loss of stability (P = 0.1284);
MVP		0.82
MPC		0.36
ClinPred		0.95	D
GERP RS		5.7
Varity_R		0.77
gMVP		0.71

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: rs1555525941; hg19: chr17-10542260;