1-2556695-C-A

Variant names:

• chr1-2556695-C-A
• NM_003820.4:c.31C>A

Variant summary

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

The NM_003820.4(TNFRSF14):​c.31C>A​(p.Pro11Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,300 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. 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. P11S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TNFRSF14 NM_003820.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.02

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]

TNFRSF14-AS1 (HGNC:26966): (TNFRSF14 antisense RNA 1)

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=0.32164454).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF14	NM_003820.4	c.31C>A	p.Pro11Thr	missense_variant	Exon 1 of 8	ENST00000355716.5	NP_003811.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF14	ENST00000355716.5	c.31C>A	p.Pro11Thr	missense_variant	Exon 1 of 8	1	NM_003820.4	ENSP00000347948.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456300 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724078

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	0.0028	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	5.7
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	T;T;T;T;.;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.044	N
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.32	T;T;T;T;T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.2	.;.;.;.;.;M
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.2	N;N;N;N;N;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.010	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.41	.;.;.;.;.;B
Vest4		0.22, 0.18
MutPred		0.45		Gain of phosphorylation at P11 (P = 0.0078);Gain of phosphorylation at P11 (P = 0.0078);Gain of phosphorylation at P11 (P = 0.0078);Gain of phosphorylation at P11 (P = 0.0078);Gain of phosphorylation at P11 (P = 0.0078);Gain of phosphorylation at P11 (P = 0.0078);
MVP		0.72
MPC		0.56
ClinPred		0.44	T
GERP RS		0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.069
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-2488134;