3-86968770-A-T

Position:

• chr3-86968770-A-T

Variant summary

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

The ENST00000398399.7(VGLL3):​c.757T>A​(p.Ser253Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 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)
• Consequence: VGLL3 ENST00000398399.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56

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=0.21225819).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VGLL3	NM_016206.4	c.757T>A	p.Ser253Thr	missense_variant	3/4	ENST00000398399.7	NP_057290.2
VGLL3	NM_001320493.2	c.757T>A	p.Ser253Thr	missense_variant	3/4		NP_001307422.1
VGLL3	NM_001320494.2	c.598T>A	p.Ser200Thr	missense_variant	3/4		NP_001307423.1
VGLL3	XM_006713138.5	c.754T>A	p.Ser252Thr	missense_variant	3/4		XP_006713201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VGLL3	ENST00000398399.7	c.757T>A	p.Ser253Thr	missense_variant	3/4	1	NM_016206.4	ENSP00000381436	P1
VGLL3	ENST00000383698.3	c.757T>A	p.Ser253Thr	missense_variant	3/4	1		ENSP00000373199
VGLL3	ENST00000494229.1	c.559T>A	p.Ser187Thr	missense_variant	3/3	3		ENSP00000419115

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Jan 22, 2024

The c.757T>A (p.S253T) alteration is located in exon 3 (coding exon 3) of the VGLL3 gene. This alteration results from a T to A substitution at nucleotide position 757, causing the serine (S) at amino acid position 253 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	0.082
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0063	T;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.63	N;N
REVEL	Benign	0.21
Sift	Benign	0.40	T;T
Sift4G	Benign	0.60	T;T
Polyphen		0.99	D;.
Vest4		0.26
MutPred		0.30		Loss of glycosylation at S253 (P = 0.029);Loss of glycosylation at S253 (P = 0.029);
MVP		0.43
MPC		0.11
ClinPred		0.44	T
GERP RS		5.9
Varity_R		0.086
gMVP		0.25

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: chr3-87017920;