17-7559238-G-A

Variant summary

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

The NM_003808.4(TNFSF13):c.199G>A(p.Gly67Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 1,609,662 control chromosomes in the GnomAD database, including 14,667 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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 0.12 (1232 hom., cov: 31)
  • Exomes 𝑓: 0.13 (13435 hom.)
• Consequence: TNFSF13 NM_003808.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.02

Genes affected

TNFSF13 (HGNC:11928): (TNF superfamily member 13) The protein encoded by this gene is a member of the tumor necrosis factor (TNF) ligand family. This protein is a ligand for TNFRSF17/BCMA, a member of the TNF receptor family. This protein and its receptor are both found to be important for B cell development. In vitro experiments suggested that this protein may be able to induce apoptosis through its interaction with other TNF receptor family proteins such as TNFRSF6/FAS and TNFRSF14/HVEM. Alternative splicing results in multiple transcript variants. Some transcripts that skip the last exon of the upstream gene (TNFSF12) and continue into the second exon of this gene have been identified; such read-through transcripts are contained in GeneID 407977, TNFSF12-TNFSF13. [provided by RefSeq, Oct 2010]

TNFSF12-TNFSF13 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029675663).
• BP6: Variant 17-7559238-G-A is Benign according to our data. Variant chr17-7559238-G-A is described in ClinVar as [Benign]. Clinvar id is 1181749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.312 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFSF13	NM_003808.4	c.199G>A	p.Gly67Arg	missense_variant	1/6	ENST00000338784.9
TNFSF12-TNFSF13	NM_172089.4	c.499-386G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFSF13	ENST00000338784.9	c.199G>A	p.Gly67Arg	missense_variant	1/6	1	NM_003808.4	P3

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17521 AN: 152118 Hom.: 1227 Cov.: 31

Gnomad AFR AF: 0.0873

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.0718

Gnomad FIN AF: 0.0707

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.108

GnomAD3 exomes AF: 0.132 AC: 31752 AN: 240328 Hom.: 2706 AF XY: 0.125 AC XY: 16465 AN XY: 131372

Gnomad AFR exome AF: 0.0849

Gnomad AMR exome AF: 0.191

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.329

Gnomad SAS exome AF: 0.0619

Gnomad FIN exome AF: 0.0752

Gnomad NFE exome AF: 0.119

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.126 AC: 183442 AN: 1457426 Hom.: 13435 Cov.: 31 AF XY: 0.123 AC XY: 88819 AN XY: 724914

Gnomad4 AFR exome AF: 0.0844

Gnomad4 AMR exome AF: 0.184

Gnomad4 ASJ exome AF: 0.124

Gnomad4 EAS exome AF: 0.370

Gnomad4 SAS exome AF: 0.0620

Gnomad4 FIN exome AF: 0.0778

Gnomad4 NFE exome AF: 0.124

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.115 AC: 17537 AN: 152236 Hom.: 1232 Cov.: 31 AF XY: 0.114 AC XY: 8520 AN XY: 74432

Gnomad4 AFR AF: 0.0874

Gnomad4 AMR AF: 0.156

Gnomad4 ASJ AF: 0.122

Gnomad4 EAS AF: 0.325

Gnomad4 SAS AF: 0.0723

Gnomad4 FIN AF: 0.0707

Gnomad4 NFE AF: 0.117

Gnomad4 OTH AF: 0.107

Alfa AF: 0.109 Hom.: 1591

Bravo AF: 0.129

TwinsUK AF: 0.121 AC: 448

ALSPAC AF: 0.130 AC: 500

ESP6500AA AF: 0.0828 AC: 356

ESP6500EA AF: 0.110 AC: 932

ExAC AF: 0.127 AC: 15299

Asia WGS AF: 0.160 AC: 555 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 28% of patients studied by a panel of primary immunodeficiencies. Number of patients: 27. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

This variant is associated with the following publications: (PMID: 23118916) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	15
Dann	Benign	0.71
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.094	T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0030	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	8.6e-9	P;P;P;P;P;P;P;P
PROVEAN	Benign	-0.090	N;N;N;N;N;N;.;N
REVEL	Uncertain	0.34
Sift	Benign	0.42	T;T;T;T;T;T;.;T
Sift4G	Benign	0.82	T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;B;B;.;B
Vest4		0.070
MutPred		0.088		Gain of solvent accessibility (P = 0.0037);.;.;.;Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);
MPC		0.38
ClinPred		0.0037	T
GERP RS		2.2
Varity_R		0.042
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs11552708; hg19: chr17-7462555; COSMIC: COSV99547478; COSMIC: COSV99547478;