NM_003808.4:c.199G>A

Variant names:

• chr17-7559238-G-A
• rs11552708
• NM_003808.4:c.199G>A

Variant summary

Our verdict is Benign. The variant received -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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:3
• Conservation: PhyloP100: 1.02
• Publications: 66 publications found

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:33537): (TNFSF12-TNFSF13 readthrough) This gene encodes a member of the tumor necrosis factor superfamily. It encodes a hybrid protein composed of the cytoplasmic and transmembrane domains of family member 12 fused to the C-terminal domain of family member 13. The hybrid protein is membrane anchored and presents the receptor-binding domain of family member 13 at the cell surface. It stimulates cycling in T- and B-lymphoma cell lines. [provided by RefSeq, Jul 2008]

ENSG00000276384 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
TNFSF13	NM_003808.4	c.199G>A	p.Gly67Arg	missense_variant	Exon 1 of 6	ENST00000338784.9	NP_003799.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFSF13	ENST00000338784.9	c.199G>A	p.Gly67Arg	missense_variant	Exon 1 of 6	1	NM_003808.4	ENSP00000343505.4
TNFSF12-TNFSF13	ENST00000293826.4	c.499-386G>A		intron_variant	Intron 6 of 10	1		ENSP00000293826.4

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

GnomAD2 exomes AF: 0.132 AC: 31752 AN: 240328 AF XY: 0.125

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 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

African (AFR) AF: 0.0844 AC: 2818 AN: 33404

American (AMR) AF: 0.184 AC: 8150 AN: 44292

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 3240 AN: 26082

East Asian (EAS) AF: 0.370 AC: 14643 AN: 39622

South Asian (SAS) AF: 0.0620 AC: 5329 AN: 85962

European-Finnish (FIN) AF: 0.0778 AC: 4080 AN: 52440

Middle Eastern (MID) AF: 0.0710 AC: 320 AN: 4510

European-Non Finnish (NFE) AF: 0.124 AC: 137469 AN: 1110970

Other (OTH) AF: 0.123 AC: 7393 AN: 60144

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

African (AFR) AF: 0.0874 AC: 3630 AN: 41540

American (AMR) AF: 0.156 AC: 2388 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 425 AN: 3470

East Asian (EAS) AF: 0.325 AC: 1676 AN: 5150

South Asian (SAS) AF: 0.0723 AC: 349 AN: 4826

European-Finnish (FIN) AF: 0.0707 AC: 750 AN: 10614

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.117 AC: 7988 AN: 68008

Other (OTH) AF: 0.107 AC: 226 AN: 2116

Alfa AF: 0.112 Hom.: 2449

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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
DEOGEN2	Benign	0.019	.;.;T;.;.;T;.;.
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
MutationAssessor	Benign	-1.7	.;.;.;.;N;N;N;N
PhyloP100		1.0
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
PromoterAI		0.010	Neutral
Varity_R		0.042
gMVP		0.11
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11552708; hg19: chr17-7462555; COSMIC: COSV99547478; COSMIC: COSV99547478;