chrX-123885938-T-C

Variant names:

• chrX-123885938-T-C
• rs45575532
• NM_001167.4:c.276T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001167.4(XIAP):​c.276T>C​(p.Phe92Phe) variant causes a synonymous change. The variant allele was found at a frequency of 0.00121 in 1,210,110 control chromosomes in the GnomAD database, including 1 homozygotes. There are 466 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., 23 hem., cov: 23)
  • Exomes 𝑓: 0.0013 (1 hom. 443 hem.)
• Consequence: XIAP NM_001167.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.66
• Publications: 1 publications found

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]

XIAP Gene-Disease associations (from GenCC):

• X-linked lymphoproliferative disease due to XIAP deficiency

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant X-123885938-T-C is Benign according to our data. Variant chrX-123885938-T-C is described in ClinVar as Benign. ClinVar VariationId is 533657.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000805 (90/111859) while in subpopulation NFE AF = 0.00147 (78/53154). AF 95% confidence interval is 0.0012. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 23 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001167.4. 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
	XIAP	NM_001167.4	MANE Select	c.276T>C	p.Phe92Phe	synonymous	Exon 2 of 7	NP_001158.2
	XIAP	NM_001204401.2		c.276T>C	p.Phe92Phe	synonymous	Exon 2 of 7	NP_001191330.1	P98170
	XIAP	NM_001378590.1		c.276T>C	p.Phe92Phe	synonymous	Exon 2 of 7	NP_001365519.1	P98170

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XIAP	ENST00000371199.8	TSL:1 MANE Select	c.276T>C	p.Phe92Phe	synonymous	Exon 2 of 7	ENSP00000360242.3	P98170
	XIAP	ENST00000497640.1	TSL:1	n.100-2681T>C		intron	N/A
	XIAP	ENST00000355640.3	TSL:5	c.276T>C	p.Phe92Phe	synonymous	Exon 2 of 7	ENSP00000347858.3	P98170

Frequencies

GnomAD3 genomes AF: 0.000805 AC: 90 AN: 111805 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000193

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: 0.00147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000589 AC: 108 AN: 183451 AF XY: 0.000560

Gnomad AFR exome AF: 0.000760

Gnomad AMR exome AF: 0.0000729

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00125 AC: 1375 AN: 1098251 Hom.: 1 Cov.: 31 AF XY: 0.00122 AC XY: 443 AN XY: 363607

African (AFR) AF: 0.000454 AC: 12 AN: 26403

American (AMR) AF: 0.000142 AC: 5 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.000103 AC: 2 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54149

European-Finnish (FIN) AF: 0.000123 AC: 5 AN: 40520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00155 AC: 1304 AN: 842147

Other (OTH) AF: 0.00102 AC: 47 AN: 46097

GnomAD4 genome AF: 0.000805 AC: 90 AN: 111859 Hom.: 0 Cov.: 23 AF XY: 0.000675 AC XY: 23 AN XY: 34061

African (AFR) AF: 0.000324 AC: 10 AN: 30872

American (AMR) AF: 0.000192 AC: 2 AN: 10399

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3586

South Asian (SAS) AF: 0.00 AC: 0 AN: 2713

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6049

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.00147 AC: 78 AN: 53154

Other (OTH) AF: 0.00 AC: 0 AN: 1538

Alfa AF: 0.000914 Hom.: 7

Bravo AF: 0.000703

EpiCase AF: 0.00169

EpiControl AF: 0.00130

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	X-linked lymphoproliferative disease due to XIAP deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	11
DANN	Benign	0.68
PhyloP100		3.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs45575532; hg19: chrX-123019788; COSMIC: COSV63024158; COSMIC: COSV63024158;