chr3-86968650-C-T

Variant names:

• chr3-86968650-C-T
• rs779567619
• NM_016206.4:c.877G>A

Variant summary

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

The NM_016206.4(VGLL3):​c.877G>A​(p.Ala293Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: VGLL3 NM_016206.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.92

Genes affected

VGLL3 (HGNC:24327): (vestigial like family member 3) Predicted to enable protein C-terminus binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VGLL3	NM_016206.4	c.877G>A	p.Ala293Thr	missense_variant	Exon 3 of 4	ENST00000398399.7	NP_057290.2
VGLL3	NM_001320493.2	c.877G>A	p.Ala293Thr	missense_variant	Exon 3 of 4		NP_001307422.1
VGLL3	NM_001320494.2	c.718G>A	p.Ala240Thr	missense_variant	Exon 3 of 4		NP_001307423.1
VGLL3	XM_006713138.5	c.874G>A	p.Ala292Thr	missense_variant	Exon 3 of 4		XP_006713201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VGLL3	ENST00000398399.7	c.877G>A	p.Ala293Thr	missense_variant	Exon 3 of 4	1	NM_016206.4	ENSP00000381436.2
VGLL3	ENST00000383698.3	c.877G>A	p.Ala293Thr	missense_variant	Exon 3 of 4	1		ENSP00000373199.3
VGLL3	ENST00000494229.1	c.*53G>A		downstream_gene_variant		3		ENSP00000419115.1
VGLL3	ENST00000637106.1	n.-21G>A		upstream_gene_variant		5		ENSP00000489678.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249350 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135282

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.877G>A (p.A293T) alteration is located in exon 3 (coding exon 3) of the VGLL3 gene. This alteration results from a G to A substitution at nucleotide position 877, causing the alanine (A) at amino acid position 293 to be replaced by a threonine (T). 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	0.093
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.072
Sift	Benign	0.29	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.61	P;.
Vest4		0.65
MutPred		0.38		Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);
MVP		0.53
MPC		0.35
ClinPred		0.56	D
GERP RS		5.8
Varity_R		0.077
gMVP		0.36

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

LitVar

Other links and lift over

dbSNP: rs779567619; hg19: chr3-87017800;