3-11559374-A-C

Variant names:

• chr3-11559374-A-C
• NM_001128219.3:c.577T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001128219.3(VGLL4):​c.577T>G​(p.Cys193Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000214 in 1,401,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: VGLL4 NM_001128219.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.11

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2349233).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VGLL4	NM_001128219.3	c.577T>G	p.Cys193Gly	missense_variant	Exon 4 of 5	ENST00000430365.7	NP_001121691.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VGLL4	ENST00000430365.7	c.577T>G	p.Cys193Gly	missense_variant	Exon 4 of 5	2	NM_001128219.3	ENSP00000404251.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1401620 Hom.: 0 Cov.: 31 AF XY: 0.00000434 AC XY: 3 AN XY: 691676

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.25e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.577T>G (p.C193G) alteration is located in exon 4 (coding exon 4) of the VGLL4 gene. This alteration results from a T to G substitution at nucleotide position 577, causing the cysteine (C) at amino acid position 193 to be replaced by a glycine (G). 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	Benign	0.21
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.053	T;T;.;.;.;T;T;.;.
Eigen	Benign	0.0089
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T;T;T;T;T;T;T;T;D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.6	N;N;N;N;N;.;D;D;D
REVEL	Benign	0.20
Sift	Benign	0.066	T;T;T;T;T;.;D;D;D
Sift4G	Benign	0.22	T;T;T;.;T;T;.;.;D
Polyphen		0.015, 0.0050, 0.056	.;.;B;B;B;.;.;.;.
Vest4		0.47
MutPred		0.36		.;.;.;.;Gain of relative solvent accessibility (P = 0.0023);.;.;.;.;
MVP		0.17
MPC		0.26
ClinPred		0.78	D
GERP RS		5.7
gMVP		0.50

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: chr3-11600848;