chr1-173186569-C-T

Variant names:

• chr1-173186569-C-T
• NM_003326.5:c.499G>A

Variant summary

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

The NM_003326.5(TNFSF4):​c.499G>A​(p.Gly167Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TNFSF4 NM_003326.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.392
• Publications: 0 publications found

Genes affected

TNFSF4 (HGNC:11934): (TNF superfamily member 4) This gene encodes a cytokine of the tumor necrosis factor (TNF) ligand family. The encoded protein functions in T cell antigen-presenting cell (APC) interactions and mediates adhesion of activated T cells to endothelial cells. Polymorphisms in this gene have been associated with Sjogren's syndrome and systemic lupus erythematosus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

TNFSF4 Gene-Disease associations (from GenCC):

• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet
• myocardial infarction, susceptibility to

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

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=0.23753).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003326.5. 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
	TNFSF4	NM_003326.5	MANE Select	c.499G>A	p.Gly167Ser	missense	Exon 3 of 3	NP_003317.1	P23510-1
	TNFSF4	NM_001297562.2		c.349G>A	p.Gly117Ser	missense	Exon 3 of 3	NP_001284491.1	P23510-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF4	ENST00000281834.4	TSL:1 MANE Select	c.499G>A	p.Gly167Ser	missense	Exon 3 of 3	ENSP00000281834.3	P23510-1
	TNFSF4	ENST00000367718.5	TSL:1	c.349G>A	p.Gly117Ser	missense	Exon 3 of 3	ENSP00000356691.1	P23510-2
	TNFSF4	ENST00000714430.1		c.499G>A	p.Gly167Ser	missense	Exon 7 of 7	ENSP00000519699.1	P23510-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461832 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

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	0.25
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.39
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.35
Sift	Benign	0.058	T
Sift4G	Benign	0.49	T
Polyphen		0.86	P
Vest4		0.11
MutPred		0.42		Gain of sheet (P = 0.0827)
MVP		0.98
MPC		0.94
ClinPred		0.91	D
GERP RS		3.5
Varity_R		0.15
gMVP		0.39
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

hg19: chr1-173155708;