3-86968890-A-T

Variant names:

• chr3-86968890-A-T
• rs767264996
• NM_016206.4:c.637T>A

Variant summary

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

The NM_016206.4(VGLL3):​c.637T>A​(p.Ser213Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,894 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: 0.0000014 (0 hom.)
• Consequence: VGLL3 NM_016206.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.15

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.637T>A	p.Ser213Thr	missense_variant	Exon 3 of 4	ENST00000398399.7	NP_057290.2
VGLL3	NM_001320493.2	c.637T>A	p.Ser213Thr	missense_variant	Exon 3 of 4		NP_001307422.1
VGLL3	NM_001320494.2	c.478T>A	p.Ser160Thr	missense_variant	Exon 3 of 4		NP_001307423.1
VGLL3	XM_006713138.5	c.634T>A	p.Ser212Thr	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.637T>A	p.Ser213Thr	missense_variant	Exon 3 of 4	1	NM_016206.4	ENSP00000381436.2
VGLL3	ENST00000383698.3	c.637T>A	p.Ser213Thr	missense_variant	Exon 3 of 4	1		ENSP00000373199.3
VGLL3	ENST00000494229.1	c.436T>A	p.Ser146Thr	missense_variant	Exon 3 of 3	3		ENSP00000419115.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727248

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

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

Jan 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.637T>A (p.S213T) 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 637, causing the serine (S) at amino acid position 213 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	0.15
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.14
Sift	Benign	0.099	T;T
Sift4G	Benign	0.068	T;D
Polyphen		0.79	P;.
Vest4		0.55
MutPred		0.25		Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);
MVP		0.47
MPC		0.37
ClinPred		0.88	D
GERP RS		5.8
Varity_R		0.21
gMVP		0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs767264996; hg19: chr3-87018040;