chr17-6760434-A-G

Position:

• chr17-6760434-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000361842.8(XAF1):​c.254A>G​(p.Glu85Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,608,500 control chromosomes in the GnomAD database, including 1,181 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.052 (593 hom., cov: 32)
  • Exomes 𝑓: 0.0084 (588 hom.)
• Consequence: XAF1 ENST00000361842.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.236

Genes affected

XAF1 (HGNC:30932): (XIAP associated factor 1) This gene encodes a protein which binds to and counteracts the inhibitory effect of a member of the IAP (inhibitor of apoptosis) protein family. IAP proteins bind to and inhibit caspases which are activated during apoptosis. The proportion of IAPs and proteins which interfere with their activity, such as the encoded protein, affect the progress of the apoptosis signaling pathway. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022321045).
• BP6: Variant 17-6760434-A-G is Benign according to our data. Variant chr17-6760434-A-G is described in ClinVar as [Benign]. Clinvar id is 1243178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XAF1	NM_017523.5	c.254A>G	p.Glu85Gly	missense_variant	4/7	ENST00000361842.8	NP_059993.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XAF1	ENST00000361842.8	c.254A>G	p.Glu85Gly	missense_variant	4/7	1	NM_017523.5	ENSP00000354822	P1

Frequencies

GnomAD3 genomes AF: 0.0520 AC: 7827 AN: 150576 Hom.: 588 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0273

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00669

Gnomad SAS AF: 0.0187

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.00249

Gnomad OTH AF: 0.0520

GnomAD3 exomes AF: 0.0183 AC: 4575 AN: 249914 Hom.: 255 AF XY: 0.0152 AC XY: 2057 AN XY: 135186

Gnomad AFR exome AF: 0.175

Gnomad AMR exome AF: 0.0166

Gnomad ASJ exome AF: 0.0154

Gnomad EAS exome AF: 0.00649

Gnomad SAS exome AF: 0.0162

Gnomad FIN exome AF: 0.00236

Gnomad NFE exome AF: 0.00274

Gnomad OTH exome AF: 0.0152

GnomAD4 exome AF: 0.00838 AC: 12218 AN: 1457846 Hom.: 588 Cov.: 37 AF XY: 0.00802 AC XY: 5814 AN XY: 725242

Gnomad4 AFR exome AF: 0.176

Gnomad4 AMR exome AF: 0.0176

Gnomad4 ASJ exome AF: 0.0160

Gnomad4 EAS exome AF: 0.0167

Gnomad4 SAS exome AF: 0.0152

Gnomad4 FIN exome AF: 0.00235

Gnomad4 NFE exome AF: 0.00168

Gnomad4 OTH exome AF: 0.0179

GnomAD4 genome AF: 0.0521 AC: 7849 AN: 150654 Hom.: 593 Cov.: 32 AF XY: 0.0513 AC XY: 3772 AN XY: 73464

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.0273

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.00651

Gnomad4 SAS AF: 0.0183

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.00249

Gnomad4 OTH AF: 0.0521

Alfa AF: 0.0134 Hom.: 194

Bravo AF: 0.0593

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.173 AC: 764

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.0215 AC: 2617

Asia WGS AF: 0.0260 AC: 92 AN: 3478

EpiCase AF: 0.00376

EpiControl AF: 0.00368

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2020	This variant is associated with the following publications: (PMID: 23645777) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T;.;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.67	T;T;T
MetaRNN	Benign	0.0022	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	.;.;L
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.8	.;D;D
REVEL	Benign	0.023
Sift	Uncertain	0.021	.;D;D
Sift4G	Benign	0.28	T;T;T
Polyphen		0.64, 0.69	.;P;P
Vest4		0.21, 0.078
MPC		0.34
ClinPred		0.034	T
GERP RS		0.35
Varity_R		0.089
gMVP		0.18

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: rs34195599; hg19: chr17-6663753;