1-2556714-A-G

Variant names:

• chr1-2556714-A-G
• rs4870
• NM_003820.4:c.50A>G

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• 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
• Publications: 66 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003820.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF14	NM_003820.4	MANE Select	c.50A>G	p.Lys17Arg	missense	Exon 1 of 8	NP_003811.2
	TNFRSF14	NM_001297605.2		c.50A>G	p.Lys17Arg	missense	Exon 1 of 7	NP_001284534.1
	TNFRSF14-AS1	NR_037844.2		n.36-18T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF14	ENST00000355716.5	TSL:1 MANE Select	c.50A>G	p.Lys17Arg	missense	Exon 1 of 8	ENSP00000347948.4
	TNFRSF14	ENST00000475523.5	TSL:1	n.70+259A>G		intron	N/A
	TNFRSF14	ENST00000434817.5	TSL:3	c.50A>G	p.Lys17Arg	missense	Exon 2 of 7	ENSP00000415254.1

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

GnomAD2 exomes AF: 0.514 AC: 121076 AN: 235732 AF XY: 0.514

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 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

African (AFR) AF: 0.731 AC: 24212 AN: 33128

American (AMR) AF: 0.511 AC: 22193 AN: 43448

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 11553 AN: 25422

East Asian (EAS) AF: 0.489 AC: 19331 AN: 39534

South Asian (SAS) AF: 0.624 AC: 52692 AN: 84504

European-Finnish (FIN) AF: 0.479 AC: 25190 AN: 52592

Middle Eastern (MID) AF: 0.539 AC: 3070 AN: 5696

European-Non Finnish (NFE) AF: 0.478 AC: 528937 AN: 1106432

Other (OTH) AF: 0.513 AC: 30657 AN: 59800

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

African (AFR) AF: 0.719 AC: 29840 AN: 41492

American (AMR) AF: 0.538 AC: 8229 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 1566 AN: 3468

East Asian (EAS) AF: 0.501 AC: 2583 AN: 5158

South Asian (SAS) AF: 0.640 AC: 3078 AN: 4808

European-Finnish (FIN) AF: 0.497 AC: 5258 AN: 10572

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.474 AC: 32221 AN: 67944

Other (OTH) AF: 0.529 AC: 1115 AN: 2106

Alfa AF: 0.498 Hom.: 21797

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

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.014	N
MetaRNN	Benign	0.0000027	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.2	L
PhyloP100		-1.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.15
Sift	Benign	0.47	T
Sift4G	Benign	0.18	T
Polyphen		0.39	B
Vest4		0.030
MPC		0.14
ClinPred		0.0080	T
GERP RS		-1.1
PromoterAI		0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.033
gMVP		0.42
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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