rs1555525941

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP5_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

Scores

5
10
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.21
Variant links:
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]

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ACMG classification

Classification made for transcript

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
MYH3NM_002470.4 linkc.3269A>C p.Gln1090Pro missense_variant 26/41 ENST00000583535.6 NP_002461.2 P11055Q5GJ67
MYH3XM_011523870.4 linkc.3269A>C p.Gln1090Pro missense_variant 26/41 XP_011522172.1 P11055
MYH3XM_011523871.3 linkc.3269A>C p.Gln1090Pro missense_variant 26/41 XP_011522173.1 P11055
MYH3XM_047436127.1 linkc.3269A>C p.Gln1090Pro missense_variant 28/43 XP_047292083.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYH3ENST00000583535.6 linkc.3269A>C p.Gln1090Pro missense_variant 26/415 NM_002470.4 ENSP00000464317.1 P11055

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
LINK: link

Submissions by phenotype

Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsApr 24, 2017- -

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555525941; hg19: chr17-10542260; API