1-2556686-G-A

Variant names:

• chr1-2556686-G-A
• NM_003820.4:c.22G>A

Variant summary

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

The NM_003820.4(TNFRSF14):​c.22G>A​(p.Gly8Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TNFRSF14 NM_003820.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.334

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2559328).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF14	NM_003820.4	c.22G>A	p.Gly8Arg	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.22G>A	p.Gly8Arg	missense_variant	Exon 1 of 8	1	NM_003820.4	ENSP00000347948.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.22G>A (p.G8R) alteration is located in exon 1 (coding exon 1) of the TNFRSF14 gene. This alteration results from a G to A substitution at nucleotide position 22, causing the glycine (G) at amino acid position 8 to be replaced by an arginine (R). 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	0.14
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T;T;T;T;.;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.19	N
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.26	T;T;T;T;T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.6	.;.;.;.;.;L
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.5	N;N;N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.038	D;D;D;D;T;D
Sift4G	Uncertain	0.060	T;T;T;T;D;T
Polyphen		0.98	.;.;.;.;.;D
Vest4		0.25, 0.19
MutPred		0.16		Loss of catalytic residue at W7 (P = 0.1645);Loss of catalytic residue at W7 (P = 0.1645);Loss of catalytic residue at W7 (P = 0.1645);Loss of catalytic residue at W7 (P = 0.1645);Loss of catalytic residue at W7 (P = 0.1645);Loss of catalytic residue at W7 (P = 0.1645);
MVP		0.68
MPC		0.23
ClinPred		0.43	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.039
gMVP		0.49

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: chr1-2488125;