chr3-11601879-C-T

Position:

• chr3-11601879-C-T

Variant summary

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

The NM_001128219.3(VGLL4):​c.226G>A​(p.Asp76Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,516 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: 6.8e-7 (0 hom.)
• Consequence: VGLL4 NM_001128219.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.38

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]

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=0.121370286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VGLL4	NM_001128219.3	c.226G>A	p.Asp76Asn	missense_variant	2/5	ENST00000430365.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VGLL4	ENST00000430365.7	c.226G>A	p.Asp76Asn	missense_variant	2/5	2	NM_001128219.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461516 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 727088

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2022

The c.226G>A (p.D76N) alteration is located in exon 2 (coding exon 2) of the VGLL4 gene. This alteration results from a G to A substitution at nucleotide position 226, causing the aspartic acid (D) at amino acid position 76 to be replaced by an asparagine (N). 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	0.097
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	T;T;.;T;T;.;.;T;T;.;T;T
Eigen	Benign	-0.063
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.4	N;N;N;.;D;D;D;D;.;D;D;D
REVEL	Benign	0.064
Sift	Benign	0.083	T;T;T;.;T;T;T;T;.;T;T;T
Sift4G	Benign	0.43	T;T;T;T;.;.;T;.;T;.;.;.
Polyphen		0.0080	.;.;B;.;.;.;.;.;.;.;.;.
Vest4		0.29
MutPred		0.13		.;.;Loss of stability (P = 0.1196);.;.;.;.;.;.;.;.;.;
MVP		0.19
MPC		0.19
ClinPred		0.84	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.27

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: chr3-11643353;