rs1131532

chr3-172506513-A-Cchr3-172506513-A-Gchr3-172506513-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003810.4(TNFSF10):c.825T>G(p.Phe275Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,604,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F275F) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: TNFSF10 NM_003810.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.430

Genes affected

TNFSF10 (HGNC:11925): (TNF superfamily member 10) The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This protein preferentially induces apoptosis in transformed and tumor cells, but does not appear to kill normal cells although it is expressed at a significant level in most normal tissues. This protein binds to several members of TNF receptor superfamily including TNFRSF10A/TRAILR1, TNFRSF10B/TRAILR2, TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4, and possibly also to TNFRSF11B/OPG. The activity of this protein may be modulated by binding to the decoy receptors TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4, and TNFRSF11B/OPG that cannot induce apoptosis. The binding of this protein to its receptors has been shown to trigger the activation of MAPK8/JNK, caspase 8, and caspase 3. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFSF10	NM_003810.4	c.825T>G	p.Phe275Leu	missense_variant	5/5	ENST00000241261.7
TNFSF10	NM_001190942.2	c.*371T>G		3_prime_UTR_variant	3/3
TNFSF10	NR_033994.2	n.828T>G		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFSF10	ENST00000241261.7	c.825T>G	p.Phe275Leu	missense_variant	5/5	1	NM_003810.4	P1
TNFSF10	ENST00000420541.6	c.*371T>G		3_prime_UTR_variant	3/3	1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152020 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000206 AC: 5 AN: 242212 Hom.: 0 AF XY: 0.0000229 AC XY: 3 AN XY: 130798

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000554

Gnomad SAS exome AF: 0.0000358

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1451998 Hom.: 0 Cov.: 61 AF XY: 0.0000125 AC XY: 9 AN XY: 721860

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74392

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00573 Hom.: 18956

ExAC AF: 0.0000247 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Benign	7.3
Dann	Benign	0.96
DEOGEN2	Pathogenic	0.96	D
Eigen	Benign	-0.81
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	0.00031	P;P
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.69
Sift	Benign	0.068	T
Sift4G	Benign	0.10	T
Polyphen		0.97	D
Vest4		0.61
MutPred		0.90		Gain of sheet (P = 0.1451);
MVP		0.70
MPC		0.35
ClinPred		0.84	D
GERP RS		-7.3
Varity_R		0.81
gMVP		0.84

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: rs1131532; hg19: chr3-172224303;