22-22245287-G-T

Variant names:

• chr22-22245287-G-T
• rs1356068317
• NM_007128.4:c.388G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_007128.4(VPREB1):​c.388G>T​(p.Glu130*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: VPREB1 NM_007128.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.36
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.388G>T	p.Glu130*	stop_gained	Exon 2 of 2	NP_009059.1	P12018
	VPREB1	NM_001303509.2		c.385G>T	p.Glu129*	stop_gained	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.388G>T	p.Glu130*	stop_gained	Exon 2 of 2	ENSP00000385361.3	P12018
	VPREB1	ENST00000302273.3	TSL:3	c.*245G>T		3_prime_UTR	Exon 2 of 2	ENSP00000304590.3	F8W8C9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399064 Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0 AN XY: 691808

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31392

American (AMR) AF: 0.00 AC: 0 AN: 33754

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21728

East Asian (EAS) AF: 0.00 AC: 0 AN: 39132

South Asian (SAS) AF: 0.00 AC: 0 AN: 74874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5470

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1087214

Other (OTH) AF: 0.00 AC: 0 AN: 57872

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	34
DANN	Benign	0.95
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.069	N
PhyloP100		1.4
Vest4		0.42
GERP RS		0.89
Mutation Taster		=159/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1356068317; hg19: chr22-22599699;