1-2557788-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003820.4(TNFRSF14):c.132G>C(p.Glu44Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TNFRSF14 NM_003820.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.113

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19066757).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF14	NM_003820.4	c.132G>C	p.Glu44Asp	missense_variant	2/8	ENST00000355716.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF14	ENST00000355716.5	c.132G>C	p.Glu44Asp	missense_variant	2/8	1	NM_003820.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459500 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726010

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2024

The c.132G>C (p.E44D) alteration is located in exon 2 (coding exon 2) of the TNFRSF14 gene. This alteration results from a G to C substitution at nucleotide position 132, causing the glutamic acid (E) at amino acid position 44 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.020	T;T;T;T;.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.68	D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.19	T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N
REVEL	Benign	0.097
Sift	Benign	0.27	T;T;T;T;T;T
Sift4G	Benign	0.34	T;T;T;T;T;T
Polyphen		0.28	.;.;.;.;.;B
Vest4		0.21, 0.18
MutPred		0.29		Gain of glycosylation at S41 (P = 0.1471);Gain of glycosylation at S41 (P = 0.1471);Gain of glycosylation at S41 (P = 0.1471);Gain of glycosylation at S41 (P = 0.1471);Gain of glycosylation at S41 (P = 0.1471);Gain of glycosylation at S41 (P = 0.1471);
MVP		0.63
MPC		0.15
ClinPred		0.45	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.54

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: rs897671259; hg19: chr1-2489227;