chr7-76329603-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_012479.4(YWHAG):​c.718G>T​(p.Asp240Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D240D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

YWHAG
NM_012479.4 missense

Scores

3
11
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.87
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 Uncertain_significance. Variant got 4 ACMG points.

PM1
In a chain 14-3-3 protein gamma, N-terminally processed (size 245) in uniprot entity 1433G_HUMAN there are 18 pathogenic changes around while only 3 benign (86%) in NM_012479.4
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
YWHAGNM_012479.4 linkc.718G>T p.Asp240Tyr missense_variant Exon 2 of 2 ENST00000307630.5 NP_036611.2 P61981

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
YWHAGENST00000307630.5 linkc.718G>T p.Asp240Tyr missense_variant Exon 2 of 2 1 NM_012479.4 ENSP00000306330.3 P61981

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Nov 28, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.718G>T (p.D240Y) alteration is located in exon 2 (coding exon 2) of the YWHAG gene. This alteration results from a G to T substitution at nucleotide position 718, causing the aspartic acid (D) at amino acid position 240 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.54
BayesDel_addAF
Uncertain
0.10
D
BayesDel_noAF
Benign
-0.090
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.81
D
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D
M_CAP
Benign
0.056
D
MetaRNN
Uncertain
0.64
D
MetaSVM
Benign
-0.75
T
MutationAssessor
Uncertain
2.4
M
PrimateAI
Pathogenic
0.83
D
PROVEAN
Uncertain
-3.1
D
REVEL
Benign
0.28
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.022
D
Polyphen
0.98
D
Vest4
0.55
MutPred
0.42
Loss of disorder (P = 0.0196);
MVP
0.77
MPC
2.7
ClinPred
0.99
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.64
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: chr7-75958920; API