3-11564850-C-A

Variant names:

• chr3-11564850-C-A
• rs750870490
• NM_001128219.3:c.442G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001128219.3(VGLL4):​c.442G>T​(p.Ala148Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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. A148T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: VGLL4 NM_001128219.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.282
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.036271363).

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.442G>T	p.Ala148Ser	missense	Exon 3 of 5	NP_001121691.1	Q14135-4
	VGLL4	NM_001284390.2		c.439G>T	p.Ala147Ser	missense	Exon 5 of 7	NP_001271319.1	A0A0A6YYI5
	VGLL4	NM_014667.4		c.424G>T	p.Ala142Ser	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.442G>T	p.Ala148Ser	missense	Exon 3 of 5	ENSP00000404251.2	Q14135-4
	VGLL4	ENST00000426568.5	TSL:1	c.439G>T	p.Ala147Ser	missense	Exon 5 of 7	ENSP00000413030.2	A0A0A6YYI5
	VGLL4	ENST00000273038.7	TSL:1	c.424G>T	p.Ala142Ser	missense	Exon 4 of 6	ENSP00000273038.3	Q14135-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452578 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722248

African (AFR) AF: 0.00 AC: 0 AN: 33362

American (AMR) AF: 0.00 AC: 0 AN: 43828

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25942

East Asian (EAS) AF: 0.00 AC: 0 AN: 39430

South Asian (SAS) AF: 0.00 AC: 0 AN: 85246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108836

Other (OTH) AF: 0.00 AC: 0 AN: 59982

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	2.1
DANN	Benign	0.91
DEOGEN2	Benign	0.0097	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.50	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.28
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.036
Sift	Benign	0.52	T
Sift4G	Benign	0.78	T
Polyphen		0.18	B
Vest4		0.13
MutPred		0.098		Gain of phosphorylation at A148 (P = 0.0233)
MVP		0.061
MPC		0.25
ClinPred		0.11	T
GERP RS		-0.0084
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.26
Mutation Taster		=95/5	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: rs750870490; hg19: chr3-11606324;