rs4134822

Positions:

• chr19-7627389-C-G
• chr19-7627389-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020196.3(XAB2):​c.376G>C​(p.Val126Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. V126I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: XAB2 NM_020196.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.57

Genes affected

XAB2 (HGNC:14089): (XPA binding protein 2) Involved in mRNA splicing, via spliceosome; transcription, DNA-templated; and transcription-coupled nucleotide-excision repair. Located in nucleoplasm. Part of U2-type catalytic step 2 spliceosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.10819799).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XAB2	NM_020196.3	c.376G>C	p.Val126Leu	missense_variant	4/19	ENST00000358368.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XAB2	ENST00000358368.5	c.376G>C	p.Val126Leu	missense_variant	4/19	1	NM_020196.3	P1
XAB2	ENST00000595288.5	n.882G>C		non_coding_transcript_exon_variant	1/11	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.94	L
MutationTaster	Benign	0.73	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.036
Sift	Benign	0.22	T
Sift4G	Benign	0.27	T
Polyphen		0.0030	B
Vest4		0.28
MutPred		0.45		Loss of MoRF binding (P = 0.1002);
MVP		0.23
MPC		0.50
ClinPred		0.16	T
GERP RS		0.030
Varity_R		0.095
gMVP		0.17

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: rs4134822; hg19: chr19-7692275;