3-11564909-G-A

Variant names:

• chr3-11564909-G-A
• rs964703248
• NM_001128219.3:c.383C>T

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.383C>T​(p.Thr128Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,450,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T128A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: VGLL4 NM_001128219.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.66
• 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: 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=0.09605041).

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.383C>T	p.Thr128Ile	missense	Exon 3 of 5	NP_001121691.1	Q14135-4
	VGLL4	NM_001284390.2		c.380C>T	p.Thr127Ile	missense	Exon 5 of 7	NP_001271319.1	A0A0A6YYI5
	VGLL4	NM_014667.4		c.365C>T	p.Thr122Ile	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.383C>T	p.Thr128Ile	missense	Exon 3 of 5	ENSP00000404251.2	Q14135-4
	VGLL4	ENST00000426568.5	TSL:1	c.380C>T	p.Thr127Ile	missense	Exon 5 of 7	ENSP00000413030.2	A0A0A6YYI5
	VGLL4	ENST00000273038.7	TSL:1	c.365C>T	p.Thr122Ile	missense	Exon 4 of 6	ENSP00000273038.3	Q14135-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000170 AC: 4 AN: 235102 AF XY: 0.0000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000623

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000189

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000186 AC: 27 AN: 1450252 Hom.: 0 Cov.: 32 AF XY: 0.0000250 AC XY: 18 AN XY: 720912

African (AFR) AF: 0.00 AC: 0 AN: 32946

American (AMR) AF: 0.0000693 AC: 3 AN: 43278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25804

East Asian (EAS) AF: 0.00 AC: 0 AN: 39050

South Asian (SAS) AF: 0.00 AC: 0 AN: 84980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.0000208 AC: 23 AN: 1107014

Other (OTH) AF: 0.0000167 AC: 1 AN: 59900

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.7
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.098
Sift	Uncertain	0.018	D
Sift4G	Benign	0.18	T
Polyphen		0.47	P
Vest4		0.18
MutPred		0.26		Gain of sheet (P = 0.0221)
MVP		0.12
MPC		0.29
ClinPred		0.10	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.27
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs964703248; hg19: chr3-11606383;