Variant 22-22245195-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_007128.4(VPREB1):c.296A>T(p.Tyr99Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000343 in 1,585,374 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 0 hom. )

Consequence

VPREB1
NM_007128.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.123

Variant links:

Genes affected

VPREB1 (HGNC:12709): (V-set pre-B cell surrogate light chain 1) The protein encoded by this gene belongs to the immunoglobulin superfamily and is expressed selectively at the early stages of B cell development, namely, in proB and early preB cells. This gene encodes the iota polypeptide chain that is associated with the Ig-mu chain to form a molecular complex which is expressed on the surface of pre-B cells. The complex is thought to regulate Ig gene rearrangements in the early steps of B-cell differentiation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

VPREB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.10141978).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPREB1	NM_007128.4 linkuse as main transcript	c.296A>T	p.Tyr99Phe	missense_variant	2/2	ENST00000403807.4	NP_009059.1
VPREB1	NM_001303509.2 linkuse as main transcript	c.293A>T	p.Tyr98Phe	missense_variant	2/2		NP_001290438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPREB1	ENST00000403807.4 linkuse as main transcript	c.296A>T	p.Tyr99Phe	missense_variant	2/2	1	NM_007128.4	ENSP00000385361	P2
VPREB1	ENST00000302273.2 linkuse as main transcript	c.293A>T	p.Tyr98Phe	missense_variant	2/2	3		ENSP00000304590	A2

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

151970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000187

AC:

AN:

224522

Hom.:

AF XY:

0.000225

AC XY:

AN XY:

119840

show subpopulations

Gnomad AFR exome

AF:

0.000189

Gnomad AMR exome

AF:

0.0000314

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000506

Gnomad NFE exome

AF:

0.000360

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000359

AC:

515

AN:

1433404

Hom.:

Cov.:

AF XY:

0.000333

AC XY:

236

AN XY:

709768

show subpopulations

Gnomad4 AFR exome

AF:

0.0000304

Gnomad4 AMR exome

AF:

0.0000237

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000384

Gnomad4 NFE exome

AF:

0.000451

Gnomad4 OTH exome

AF:

0.000271

GnomAD4 genome

AF:

0.000184

AC:

AN:

151970

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74224

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000304

Hom.:

Bravo

AF:

0.000196

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000190

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2022

The c.296A>T (p.Y99F) alteration is located in exon 2 (coding exon 2) of the VPREB1 gene. This alteration results from a A to T substitution at nucleotide position 296, causing the tyrosine (Y) at amino acid position 99 to be replaced by a phenylalanine (F). 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

0.11

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.28

DEOGEN2

Benign

0.16

T;T

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.20

T;T

M_CAP

Benign

0.055

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

2.0

M;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.19

Sift

Benign

0.33

T;T

Sift4G

Benign

0.52

T;T

Polyphen

1.0

D;.

Vest4

0.34

MVP

0.081

MPC

0.33

ClinPred

0.048

GERP RS

0.077

Varity_R

0.51

gMVP

0.22

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over