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rs1554616627

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_012479.4(YWHAG):​c.398A>G​(p.Tyr133Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y133S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

YWHAG
NM_012479.4 missense

Scores

15
3
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.98
Variant links:
Genes affected
YWHAG (HGNC:12852): (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma) This gene product belongs to the 14-3-3 family of proteins which mediate signal transduction by binding to phosphoserine-containing proteins. This highly conserved protein family is found in both plants and mammals, and this protein is 100% identical to the rat ortholog. It is induced by growth factors in human vascular smooth muscle cells, and is also highly expressed in skeletal and heart muscles, suggesting an important role for this protein in muscle tissue. It has been shown to interact with RAF1 and protein kinase C, proteins involved in various signal transduction pathways. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1
?
    PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a helix (size 20) in uniprot entity 1433G_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_012479.4
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM5
?
    PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr7-76329923-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 549482.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
PP2
?
    PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, YWHAG
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.976
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 7-76329923-T-C is Pathogenic according to our data. Variant chr7-76329923-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1335673.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
YWHAGNM_012479.4 linkuse as main transcriptc.398A>G p.Tyr133Cys missense_variant 2/2 ENST00000307630.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
YWHAGENST00000307630.5 linkuse as main transcriptc.398A>G p.Tyr133Cys missense_variant 2/21 NM_012479.4 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD4 exome
Cov.:
35
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.67
D
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Pathogenic
0.36
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Uncertain
0.55
D
MutationAssessor
Pathogenic
3.6
H
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-8.1
D
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.88
MutPred
0.90
Gain of catalytic residue at L134 (P = 0.0435);
MVP
0.95
MPC
2.9
ClinPred
1.0
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.97
gMVP
0.87

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-75959240; API