17-7559077-G-A

Variant names:

• chr17-7559077-G-A
• NM_003808.4:c.38G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003808.4(TNFSF13):​c.38G>A​(p.Gly13Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,427,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TNFSF13 NM_003808.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.440
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08653778).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003808.4. 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
	TNFSF13	NM_003808.4	MANE Select	c.38G>A	p.Gly13Glu	missense	Exon 1 of 6	NP_003799.1	O75888-1
	TNFSF13	NM_172088.4		c.38G>A	p.Gly13Glu	missense	Exon 1 of 7	NP_742085.1	O75888-3
	TNFSF13	NM_172087.3		c.38G>A	p.Gly13Glu	missense	Exon 1 of 5	NP_742084.1	O75888-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF13	ENST00000338784.9	TSL:1 MANE Select	c.38G>A	p.Gly13Glu	missense	Exon 1 of 6	ENSP00000343505.4	O75888-1
	TNFSF13	ENST00000396545.4	TSL:1	c.38G>A	p.Gly13Glu	missense	Exon 1 of 7	ENSP00000379794.4	O75888-3
	TNFSF13	ENST00000349228.8	TSL:1	c.38G>A	p.Gly13Glu	missense	Exon 1 of 5	ENSP00000314455.6	O75888-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1427152 Hom.: 0 Cov.: 30 AF XY: 0.00000142 AC XY: 1 AN XY: 705396

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32462

American (AMR) AF: 0.00 AC: 0 AN: 41392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24342

East Asian (EAS) AF: 0.00 AC: 0 AN: 39006

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5608

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089958

Other (OTH) AF: 0.00 AC: 0 AN: 58676

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.087	T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	1.0	L
PhyloP100		0.44
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.27
Sift	Benign	0.085	T
Sift4G	Uncertain	0.0090	D
Polyphen		0.65	P
Vest4		0.18
MutPred		0.15		Gain of solvent accessibility (P = 0.012)
MVP		0.34
MPC		0.42
ClinPred		0.12	T
GERP RS		-1.9
PromoterAI		-0.035	Neutral
Varity_R		0.069
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

hg19: chr17-7462394;