1-2556714-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003820.4(TNFRSF14):c.50A>G(p.Lys17Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 1,602,598 control chromosomes in the GnomAD database, including 204,775 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.55 (24325 hom., cov: 33)
  • Exomes 𝑓: 0.49 (180450 hom.)
• Consequence: TNFRSF14 NM_003820.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -1.27

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.6974876E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.712 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF14	NM_003820.4	c.50A>G	p.Lys17Arg	missense_variant	1/8	ENST00000355716.5
TNFRSF14-AS1	NR_037844.2	n.36-18T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF14	ENST00000355716.5	c.50A>G	p.Lys17Arg	missense_variant	1/8	1	NM_003820.4	P1
TNFRSF14-AS1	ENST00000416860.3	n.56-18T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.554 AC: 84223 AN: 151926 Hom.: 24294 Cov.: 33

Gnomad AFR AF: 0.719

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.538

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.502

Gnomad SAS AF: 0.639

Gnomad FIN AF: 0.497

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.524

GnomAD3 exomes AF: 0.514 AC: 121076 AN: 235732 Hom.: 31748 AF XY: 0.514 AC XY: 65717 AN XY: 127924

Gnomad AFR exome AF: 0.727

Gnomad AMR exome AF: 0.511

Gnomad ASJ exome AF: 0.442

Gnomad EAS exome AF: 0.491

Gnomad SAS exome AF: 0.633

Gnomad FIN exome AF: 0.489

Gnomad NFE exome AF: 0.467

Gnomad OTH exome AF: 0.495

GnomAD4 exome AF: 0.495 AC: 717835 AN: 1450556 Hom.: 180450 Cov.: 54 AF XY: 0.498 AC XY: 359180 AN XY: 720804

Gnomad4 AFR exome AF: 0.731

Gnomad4 AMR exome AF: 0.511

Gnomad4 ASJ exome AF: 0.454

Gnomad4 EAS exome AF: 0.489

Gnomad4 SAS exome AF: 0.624

Gnomad4 FIN exome AF: 0.479

Gnomad4 NFE exome AF: 0.478

Gnomad4 OTH exome AF: 0.513

GnomAD4 genome AF: 0.554 AC: 84301 AN: 152042 Hom.: 24325 Cov.: 33 AF XY: 0.556 AC XY: 41315 AN XY: 74308

Gnomad4 AFR AF: 0.719

Gnomad4 AMR AF: 0.538

Gnomad4 ASJ AF: 0.452

Gnomad4 EAS AF: 0.501

Gnomad4 SAS AF: 0.640

Gnomad4 FIN AF: 0.497

Gnomad4 NFE AF: 0.474

Gnomad4 OTH AF: 0.529

Alfa AF: 0.497 Hom.: 12431

Bravo AF: 0.557

TwinsUK AF: 0.492 AC: 1826

ALSPAC AF: 0.479 AC: 1847

ESP6500AA AF: 0.726 AC: 3193

ESP6500EA AF: 0.472 AC: 4058

ExAC AF: 0.510 AC: 61543

Asia WGS AF: 0.637 AC: 2216 AN: 3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	7.6
Dann	Benign	0.93
DEOGEN2	Benign	0.0079	T;T;T;T;.;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.014	N
MetaRNN	Benign	0.0000027	T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.59	N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.47	T;T;T;T;T;T
Sift4G	Benign	0.18	T;T;T;T;T;T
Polyphen		0.39	.;.;.;.;.;B
Vest4		0.030, 0.031
MPC		0.14
ClinPred		0.0080	T
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.033
gMVP		0.42

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: rs4870; hg19: chr1-2488153; COSMIC: COSV63186428; COSMIC: COSV63186428;