3-86968905-G-T

Position:

• chr3-86968905-G-T

Variant summary

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

The NM_016206.4(VGLL3):​c.622C>A​(p.Pro208Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: VGLL3 NM_016206.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.69

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17479053).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VGLL3	NM_016206.4	c.622C>A	p.Pro208Thr	missense_variant	3/4	ENST00000398399.7	NP_057290.2
VGLL3	NM_001320493.2	c.622C>A	p.Pro208Thr	missense_variant	3/4		NP_001307422.1
VGLL3	NM_001320494.2	c.463C>A	p.Pro155Thr	missense_variant	3/4		NP_001307423.1
VGLL3	XM_006713138.5	c.619C>A	p.Pro207Thr	missense_variant	3/4		XP_006713201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VGLL3	ENST00000398399.7	c.622C>A	p.Pro208Thr	missense_variant	3/4	1	NM_016206.4	ENSP00000381436	P1
VGLL3	ENST00000383698.3	c.622C>A	p.Pro208Thr	missense_variant	3/4	1		ENSP00000373199
VGLL3	ENST00000494229.1	c.424C>A	p.Pro142Thr	missense_variant	3/3	3		ENSP00000419115

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Jun 18, 2021

The c.622C>A (p.P208T) alteration is located in exon 3 (coding exon 3) of the VGLL3 gene. This alteration results from a C to A substitution at nucleotide position 622, causing the proline (P) at amino acid position 208 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	0.089
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.016	T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	0.094
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N;N
MutationTaster	Benign	0.96	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.54	N;N
REVEL	Benign	0.17
Sift	Benign	0.35	T;T
Sift4G	Benign	0.44	T;T
Polyphen		0.0	B;.
Vest4		0.46
MutPred		0.22		Gain of glycosylation at Y209 (P = 0.0062);Gain of glycosylation at Y209 (P = 0.0062);
MVP		0.19
MPC		0.14
ClinPred		0.52	D
GERP RS		5.8
Varity_R		0.099
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1705023221; hg19: chr3-87018055;