rs1320

chr22-22245125-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007128.4(VPREB1):c.226G>A(p.Asp76Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.048 in 1,612,980 control chromosomes in the GnomAD database, including 2,244 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.037 (173 hom., cov: 32)
  • Exomes 𝑓: 0.049 (2071 hom.)
• Consequence: VPREB1 NM_007128.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.28

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018067658).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPREB1	NM_007128.4	c.226G>A	p.Asp76Asn	missense_variant	2/2	ENST00000403807.4
VPREB1	NM_001303509.2	c.223G>A	p.Asp75Asn	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPREB1	ENST00000403807.4	c.226G>A	p.Asp76Asn	missense_variant	2/2	1	NM_007128.4	P2
VPREB1	ENST00000302273.2	c.223G>A	p.Asp75Asn	missense_variant	2/2	3		A2

Frequencies

GnomAD3 genomes AF: 0.0373 AC: 5674 AN: 152016 Hom.: 173 Cov.: 32

Gnomad AFR AF: 0.00870

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.0322

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.0635

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0561

Gnomad OTH AF: 0.0240

GnomAD3 exomes AF: 0.0390 AC: 9698 AN: 248732 Hom.: 298 AF XY: 0.0390 AC XY: 5241 AN XY: 134508

Gnomad AFR exome AF: 0.00886

Gnomad AMR exome AF: 0.0222

Gnomad ASJ exome AF: 0.0234

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0126

Gnomad FIN exome AF: 0.0647

Gnomad NFE exome AF: 0.0585

Gnomad OTH exome AF: 0.0402

GnomAD4 exome AF: 0.0491 AC: 71757 AN: 1460848 Hom.: 2071 Cov.: 33 AF XY: 0.0482 AC XY: 35037 AN XY: 726580

Gnomad4 AFR exome AF: 0.00717

Gnomad4 AMR exome AF: 0.0227

Gnomad4 ASJ exome AF: 0.0239

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0129

Gnomad4 FIN exome AF: 0.0665

Gnomad4 NFE exome AF: 0.0564

Gnomad4 OTH exome AF: 0.0414

GnomAD4 genome AF: 0.0373 AC: 5674 AN: 152132 Hom.: 173 Cov.: 32 AF XY: 0.0360 AC XY: 2679 AN XY: 74368

Gnomad4 AFR AF: 0.00867

Gnomad4 AMR AF: 0.0323

Gnomad4 ASJ AF: 0.0236

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00891

Gnomad4 FIN AF: 0.0635

Gnomad4 NFE AF: 0.0561

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.0500 Hom.: 231

Bravo AF: 0.0345

TwinsUK AF: 0.0526 AC: 195

ALSPAC AF: 0.0493 AC: 190

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.0543 AC: 467

ExAC AF: 0.0406 AC: 4934

Asia WGS AF: 0.00433 AC: 15 AN: 3476

EpiCase AF: 0.0501

EpiControl AF: 0.0501

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	9.2
Dann	Benign	0.85
DEOGEN2	Benign	0.31	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0046	N
LIST_S2	Benign	0.38	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.49	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.061
Sift	Benign	0.32	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.019	B;.
Vest4		0.018
MPC		0.059
ClinPred		0.0046	T
GERP RS		-3.7
Varity_R		0.24
gMVP		0.34

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

Other links and lift over

dbSNP: rs1320; hg19: chr22-22599537; COSMIC: COSV56426565;