NM_007128.4:c.427C>T

Variant names:

• chr22-22245326-C-T
• rs367915074
• NM_007128.4:c.427C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007128.4(VPREB1):​c.427C>T​(p.Arg143Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,484,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: VPREB1 NM_007128.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.96
• Publications: 0 publications found

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]

IGL (HGNC:5853):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051727414).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007128.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPREB1	NM_007128.4	MANE Select	c.427C>T	p.Arg143Cys	missense	Exon 2 of 2	NP_009059.1	P12018
	VPREB1	NM_001303509.2		c.424C>T	p.Arg142Cys	missense	Exon 2 of 2	NP_001290438.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPREB1	ENST00000403807.4	TSL:1 MANE Select	c.427C>T	p.Arg143Cys	missense	Exon 2 of 2	ENSP00000385361.3	P12018
	VPREB1	ENST00000302273.3	TSL:3	c.*284C>T		3_prime_UTR	Exon 2 of 2	ENSP00000304590.3	F8W8C9

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152024 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000743 AC: 7 AN: 94176 AF XY: 0.0000628

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000138

Gnomad OTH exome AF: 0.000370

GnomAD4 exome AF: 0.0000668 AC: 89 AN: 1332878 Hom.: 0 Cov.: 38 AF XY: 0.0000612 AC XY: 40 AN XY: 653628

African (AFR) AF: 0.00 AC: 0 AN: 29630

American (AMR) AF: 0.00 AC: 0 AN: 23534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19738

East Asian (EAS) AF: 0.0000273 AC: 1 AN: 36682

South Asian (SAS) AF: 0.00 AC: 0 AN: 66930

European-Finnish (FIN) AF: 0.0000274 AC: 1 AN: 36486

Middle Eastern (MID) AF: 0.000187 AC: 1 AN: 5346

European-Non Finnish (NFE) AF: 0.0000746 AC: 79 AN: 1058940

Other (OTH) AF: 0.000126 AC: 7 AN: 55592

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152024 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74244

African (AFR) AF: 0.00 AC: 0 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000260 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.42
DANN	Benign	0.81
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-3.0
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.020
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.018	D
Polyphen		0.0	B
Vest4		0.13
MVP		0.067
MPC		0.068
ClinPred		0.055	T
GERP RS		-6.8
Varity_R		0.080
gMVP		0.35
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs367915074; hg19: chr22-22599738;