19-7619624-C-T

Position:

• chr19-7619624-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_020196.3(XAB2):​c.2530G>A​(p.Val844Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000827 in 1,451,170 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: XAB2 NM_020196.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XAB2	NM_020196.3	c.2530G>A	p.Val844Met	missense_variant	19/19	ENST00000358368.5	NP_064581.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XAB2	ENST00000358368.5	c.2530G>A	p.Val844Met	missense_variant	19/19	1	NM_020196.3	ENSP00000351137.3
XAB2	ENST00000595288.5	n.4457G>A		non_coding_transcript_exon_variant	11/11	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000827 AC: 12 AN: 1451170 Hom.: 0 Cov.: 36 AF XY: 0.00000416 AC XY: 3 AN XY: 720950

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 25, 2021

The c.2530G>A (p.V844M) alteration is located in exon 19 (coding exon 19) of the XAB2 gene. This alteration results from a G to A substitution at nucleotide position 2530, causing the valine (V) at amino acid position 844 to be replaced by a methionine (M). 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	Pathogenic	0.70
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.56
MutPred		0.39		Gain of helix (P = 0.062);
MVP		0.35
MPC		1.4
ClinPred		0.95	D
GERP RS		3.6
Varity_R		0.19
gMVP		0.56

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: rs774729857; hg19: chr19-7684510;