X-123885796-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_001167.4(XIAP):c.134C>T(p.Ser45Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000256 in 1,210,223 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000026 (0 hom. 7 hem.)
• Consequence: XIAP NM_001167.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.14

Genes affected

XIAP (HGNC:592): (X-linked inhibitor of apoptosis) This gene encodes a protein that belongs to a family of apoptotic suppressor proteins. Members of this family share a conserved motif termed, baculovirus IAP repeat, which is necessary for their anti-apoptotic function. This protein functions through binding to tumor necrosis factor receptor-associated factors TRAF1 and TRAF2 and inhibits apoptosis induced by menadione, a potent inducer of free radicals, and interleukin 1-beta converting enzyme. This protein also inhibits at least two members of the caspase family of cell-death proteases, caspase-3 and caspase-7. Mutations in this gene are the cause of X-linked lymphoproliferative syndrome. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 2 and 11.[provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.086987734).
• BP6: Variant X-123885796-C-T is Benign according to our data. Variant chrX-123885796-C-T is described in ClinVar as [Benign]. Clinvar id is 2146388.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000264 (29/1098209) while in subpopulation AMR AF= 0.000795 (28/35204). AF 95% confidence interval is 0.000565. There are 0 homozygotes in gnomad4_exome. There are 7 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAdExome at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XIAP	NM_001167.4	c.134C>T	p.Ser45Leu	missense_variant	2/7	ENST00000371199.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XIAP	ENST00000371199.8	c.134C>T	p.Ser45Leu	missense_variant	2/7	1	NM_001167.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 112014 Hom.: 0 Cov.: 23 AF XY: 0.0000292 AC XY: 1 AN XY: 34196

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000192

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000147 AC: 27 AN: 183320 Hom.: 0 AF XY: 0.000103 AC XY: 7 AN XY: 67884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000948

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000264 AC: 29 AN: 1098209 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 7 AN XY: 363563

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000795

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: 0.00

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 112014 Hom.: 0 Cov.: 23 AF XY: 0.0000292 AC XY: 1 AN XY: 34196

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000192

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000491

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked lymphoproliferative disease due to XIAP deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;T;T
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D;D;.;.
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.087	T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.24	N;.;N;N
MutationTaster	Benign	0.62	D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.5	N;D;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.019	D;T;D;D
Sift4G	Benign	0.20	T;T;T;T
Polyphen		0.85	P;.;P;P
Vest4		0.17
MutPred		0.48		Loss of disorder (P = 0.0108);Loss of disorder (P = 0.0108);Loss of disorder (P = 0.0108);Loss of disorder (P = 0.0108);
MVP		0.26
MPC		0.23
ClinPred		0.14	T
GERP RS		5.8
Varity_R		0.53
gMVP		0.65

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: rs768460056; hg19: chrX-123019646;