3-11564835-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001128219.3(VGLL4):​c.457G>A​(p.Gly153Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000009 in 1,443,808 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G153R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000090 ( 1 hom. )

Consequence

VGLL4
NM_001128219.3 missense

Scores

3
15

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.64
Variant links:
Genes affected
VGLL4 (HGNC:28966): (vestigial like family member 4) Predicted to enable transcription coactivator binding activity. Involved in negative regulation of Wnt signaling pathway; negative regulation of cell growth; and negative regulation of hippo signaling. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]
ATG7 (HGNC:16935): (autophagy related 7) This gene encodes an E1-like activating enzyme that is essential for autophagy and cytoplasmic to vacuole transport. The encoded protein is also thought to modulate p53-dependent cell cycle pathways during prolonged metabolic stress. It has been associated with multiple functions, including axon membrane trafficking, axonal homeostasis, mitophagy, adipose differentiation, and hematopoietic stem cell maintenance. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1
In a modified_residue Phosphothreonine (size 0) in uniprot entity VGLL4_HUMAN
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.10819507).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VGLL4NM_001128219.3 linkc.457G>A p.Gly153Ser missense_variant Exon 3 of 5 ENST00000430365.7 NP_001121691.1 Q14135G5E9M7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VGLL4ENST00000430365.7 linkc.457G>A p.Gly153Ser missense_variant Exon 3 of 5 2 NM_001128219.3 ENSP00000404251.2 G5E9M7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000140
AC:
3
AN:
214902
Hom.:
0
AF XY:
0.0000170
AC XY:
2
AN XY:
117676
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000121
Gnomad SAS exome
AF:
0.0000353
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000900
AC:
13
AN:
1443808
Hom.:
1
Cov.:
32
AF XY:
0.00000976
AC XY:
7
AN XY:
717262
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000257
Gnomad4 SAS exome
AF:
0.0000237
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000724
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000831
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.52
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.0056
T;T;.;.;.;T;T;.;.;T
Eigen
Benign
0.14
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Benign
0.74
D
LIST_S2
Uncertain
0.86
D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.0055
T
MetaRNN
Benign
0.11
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-0.15
N;N;N;N;N;.;N;N;N;N
REVEL
Benign
0.099
Sift
Benign
0.33
T;T;T;T;T;.;T;T;T;T
Sift4G
Benign
0.71
T;T;T;.;T;T;.;.;T;.
Polyphen
0.85, 0.40
.;.;P;P;B;.;.;.;.;.
Vest4
0.15
MutPred
0.17
.;.;.;.;Gain of phosphorylation at G153 (P = 0.0066);.;.;.;.;.;
MVP
0.24
MPC
0.22
ClinPred
0.16
T
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
gMVP
0.19

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: rs754296543; hg19: chr3-11606309; COSMIC: COSV56075317; COSMIC: COSV56075317; API