Genetic Variant VGLL1:p.Ala152Thr (chrX-136548828-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_016267.4(VGLL1):c.454G>A(p.Ala152Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000264 in 1,210,413 control chromosomes in the GnomAD database, including 1 homozygotes. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000026 ( 1 hom. 12 hem. )

Consequence

VGLL1
NM_016267.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.411

Publications

1 publications found

Variant links:

Genes affected

VGLL1 (HGNC:20985): (vestigial like family member 1) The protein encoded by this gene binds proteins of the TEA domain family of transcription factors (TEFs) through the Vg (vestigial) homology region found in its N-terminus. It may thus function as a specific coactivator for the mammalian TEFs. [provided by RefSeq, Sep 2009]

VGLL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006756693).

BS2

High Hemizygotes in GnomAdExome4 at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VGLL1	NM_016267.4 link	c.454G>A	p.Ala152Thr	missense_variant	Exon 3 of 5	ENST00000370634.8	NP_057351.1	Q99990

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VGLL1	ENST00000370634.8 link	c.454G>A	p.Ala152Thr	missense_variant	Exon 3 of 5	1	NM_016267.4	ENSP00000359668.3	Q99990
VGLL1	ENST00000440515.5 link	c.346G>A	p.Ala116Thr	missense_variant	Exon 2 of 4	3		ENSP00000398360.1	H0Y5G3
VGLL1	ENST00000456412.1 link	c.41-1940G>A		intron_variant	Intron 1 of 2	3		ENSP00000388868.1	Q5H916

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

112161

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000839

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000158

AC:

AN:

183309

AF XY:

0.000133

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00195

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000245

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000264

AC:

AN:

1098252

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

363606

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26403

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.000530

AC:

AN:

30206

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54149

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40517

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00000831

AC:

AN:

842149

Other (OTH)

AF:

0.0000868

AC:

AN:

46098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000267

AC:

AN:

112161

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34335

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30827

American (AMR)

AF:

0.00

AC:

AN:

10638

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.000839

AC:

AN:

3574

South Asian (SAS)

AF:

0.00

AC:

AN:

2678

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6167

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53218

Other (OTH)

AF:

0.00

AC:

AN:

1490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000988

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 06, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.454G>A (p.A152T) alteration is located in exon 3 (coding exon 2) of the VGLL1 gene. This alteration results from a G to A substitution at nucleotide position 454, causing the alanine (A) at amino acid position 152 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

0.081

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.033

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.0076

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.38

M_CAP

Benign

0.0035

MetaRNN

Benign

0.0068

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-1.2

PhyloP100

-0.41

PrimateAI

Benign

0.25

PROVEAN

Benign

0.51

REVEL

Benign

0.040

Sift

Benign

0.61

Sift4G

Benign

0.75

Polyphen

0.010

Vest4

0.074

MutPred

0.11

Gain of glycosylation at A152 (P = 0.0043);

MVP

0.15

MPC

0.38

ClinPred

0.013

GERP RS

-4.7

Varity_R

0.035

gMVP

0.065

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over