Genetic Variant NM_016206.4:c.29C>T (chr3-86990715-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_016206.4(VGLL3):c.29C>T(p.Pro10Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000234 in 1,279,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000023 ( 0 hom. )

Consequence

VGLL3
NM_016206.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.53

Variant links:

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]

VGLL3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29794973).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VGLL3	NM_016206.4 link	c.29C>T	p.Pro10Leu	missense_variant	Exon 1 of 4	ENST00000398399.7	NP_057290.2	A8MV65-1
VGLL3	NM_001320493.2 link	c.29C>T	p.Pro10Leu	missense_variant	Exon 1 of 4		NP_001307422.1	A8MV65-2
VGLL3	NM_001320494.2 link	c.29C>T	p.Pro10Leu	missense_variant	Exon 1 of 4		NP_001307423.1
VGLL3	XM_006713138.5 link	c.29C>T	p.Pro10Leu	missense_variant	Exon 1 of 4		XP_006713201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VGLL3	ENST00000398399.7 link	c.29C>T	p.Pro10Leu	missense_variant	Exon 1 of 4	1	NM_016206.4	ENSP00000381436.2	A8MV65-1
VGLL3	ENST00000383698.3 link	c.29C>T	p.Pro10Leu	missense_variant	Exon 1 of 4	1		ENSP00000373199.3	A8MV65-2
VGLL3	ENST00000494229.1 link	c.-14C>T		upstream_gene_variant		3		ENSP00000419115.1	H7C571

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000234

AC:

AN:

1279932

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

630788

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26030

American (AMR)

AF:

0.00

AC:

AN:

20118

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20606

East Asian (EAS)

AF:

0.0000633

AC:

AN:

31578

South Asian (SAS)

AF:

0.00

AC:

AN:

51618

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48314

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4986

European-Non Finnish (NFE)

AF:

9.76e-7

AC:

AN:

1025030

Other (OTH)

AF:

0.00

AC:

AN:

51652

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 08, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.29C>T (p.P10L) alteration is located in exon 1 (coding exon 1) of the VGLL3 gene. This alteration results from a C to T substitution at nucleotide position 29, causing the proline (P) at amino acid position 10 to be replaced by a leucine (L). 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

0.18

BayesDel_addAF

Benign

-0.068

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.036

T;.

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.85

T;T

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.30

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.69

N;N

PhyloP100

3.5

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-2.4

N;N

REVEL

Benign

0.15

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.65

T;T

Polyphen

0.96

D;.

Vest4

0.45

MutPred

0.46

Loss of disorder (P = 0.0028);Loss of disorder (P = 0.0028);

MVP

0.38

MPC

0.58

ClinPred

0.82

GERP RS

4.7

PromoterAI

0.041

Neutral

(source)

Varity_R

0.22

gMVP

0.50

Mutation Taster

=90/10

polymorphism

(source)

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

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NM_016206.4:c.29C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over