3-11564835-C-T

Variant names:

• chr3-11564835-C-T
• rs754296543
• NM_001128219.3:c.457G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_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. 13/20 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.64
• Publications: 1 publications found

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]

ATG7 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia, autosomal recessive 31

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10819507).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128219.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VGLL4	NM_001128219.3	MANE Select	c.457G>A	p.Gly153Ser	missense	Exon 3 of 5	NP_001121691.1	Q14135-4
	VGLL4	NM_001284390.2		c.454G>A	p.Gly152Ser	missense	Exon 5 of 7	NP_001271319.1	A0A0A6YYI5
	VGLL4	NM_014667.4		c.439G>A	p.Gly147Ser	missense	Exon 4 of 6	NP_055482.2	Q14135-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VGLL4	ENST00000430365.7	TSL:2 MANE Select	c.457G>A	p.Gly153Ser	missense	Exon 3 of 5	ENSP00000404251.2	Q14135-4
	VGLL4	ENST00000426568.5	TSL:1	c.454G>A	p.Gly152Ser	missense	Exon 5 of 7	ENSP00000413030.2	A0A0A6YYI5
	VGLL4	ENST00000273038.7	TSL:1	c.439G>A	p.Gly147Ser	missense	Exon 4 of 6	ENSP00000273038.3	Q14135-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000140 AC: 3 AN: 214902 AF XY: 0.0000170

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33184

American (AMR) AF: 0.00 AC: 0 AN: 42540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25794

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38972

South Asian (SAS) AF: 0.0000237 AC: 2 AN: 84338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48720

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5698

European-Non Finnish (NFE) AF: 0.00000724 AC: 8 AN: 1104802

Other (OTH) AF: 0.00 AC: 0 AN: 59760

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000831 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.6
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.099
Sift	Benign	0.33	T
Sift4G	Benign	0.71	T
Polyphen		0.85	P
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
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

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