rs2234162

Positions:

• chr1-2559866-C-G
• chr1-2559866-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003820.4(TNFRSF14):​c.348C>G​(p.Asn116Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000688 in 1,454,494 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. N116N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: TNFRSF14 NM_003820.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.992

Genes affected

TNFRSF14 (HGNC:11912): (TNF receptor superfamily member 14) This gene encodes a member of the TNF (tumor necrosis factor) receptor superfamily. The encoded protein functions in signal transduction pathways that activate inflammatory and inhibitory T-cell immune response. It binds herpes simplex virus (HSV) viral envelope glycoprotein D (gD), mediating its entry into cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF14	NM_003820.4	c.348C>G	p.Asn116Lys	missense_variant	4/8	ENST00000355716.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF14	ENST00000355716.5	c.348C>G	p.Asn116Lys	missense_variant	4/8	1	NM_003820.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000427 AC: 1 AN: 234464 Hom.: 0 AF XY: 0.00000786 AC XY: 1 AN XY: 127272

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000948

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000688 AC: 10 AN: 1454494 Hom.: 0 Cov.: 34 AF XY: 0.00000692 AC XY: 5 AN XY: 722840

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000811

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000830 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Uncertain	0.48	T;D;D;D;.;D
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.084	N
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.9	.;.;.;.;.;L
MutationTaster	Benign	1.0	N;N
PROVEAN	Uncertain	-3.0	D;D;D;D;D;N
REVEL	Benign	0.29
Sift	Uncertain	0.011	D;D;D;D;D;D
Sift4G	Uncertain	0.011	D;T;T;T;T;T
Polyphen		1.0	.;.;.;.;.;D
Vest4		0.28, 0.28
MutPred		0.81		Gain of methylation at N116 (P = 0.025);Gain of methylation at N116 (P = 0.025);Gain of methylation at N116 (P = 0.025);Gain of methylation at N116 (P = 0.025);Gain of methylation at N116 (P = 0.025);Gain of methylation at N116 (P = 0.025);
MVP		0.90
MPC		0.71
ClinPred		0.54	D
GERP RS		0.11
Varity_R		0.28
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2234162; hg19: chr1-2491305;