rs193921033

chr1-12104381-G-Achr1-12104381-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001243.5(TNFRSF8):c.271G>A(p.Asp91Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D91Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TNFRSF8 NM_001243.5 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.52

Genes affected

TNFRSF8 (HGNC:11923): (TNF receptor superfamily member 8) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor is expressed by activated, but not by resting, T and B cells. TRAF2 and TRAF5 can interact with this receptor, and mediate the signal transduction that leads to the activation of NF-kappaB. This receptor is a positive regulator of apoptosis, and also has been shown to limit the proliferative potential of autoreactive CD8 effector T cells and protect the body against autoimmunity. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41393578).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF8	NM_001243.5	c.271G>A	p.Asp91Asn	missense_variant, splice_region_variant	4/15	ENST00000263932.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF8	ENST00000263932.7	c.271G>A	p.Asp91Asn	missense_variant, splice_region_variant	4/15	1	NM_001243.5	P1
TNFRSF8	ENST00000417814.3	c.-63G>A		splice_region_variant, 5_prime_UTR_variant	3/14	1
TNFRSF8	ENST00000514649.5	c.*15G>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	3/14	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251466 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.34
Sift	Benign	0.12	T
Sift4G	Benign	0.26	T
Polyphen		1.0	D
Vest4		0.38
MutPred		0.40		Loss of stability (P = 0.2249);
MVP		0.78
MPC		0.74
ClinPred		0.80	D
GERP RS		4.9
Varity_R		0.056
gMVP		0.81

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: rs193921033; hg19: chr1-12164438; COSMIC: COSV55799349;