rs2234163

Variant names:

• chr1-2559867-G-A
• rs2234163
• NM_003820.4:c.349G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-2559867-G-A
• chr1-2559867-G-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_003820.4(TNFRSF14):​c.349G>A​(p.Ala117Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00885 in 1,606,292 control chromosomes in the GnomAD database, including 142 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 0.015 (36 hom., cov: 33)
  • Exomes 𝑓: 0.0082 (106 hom.)
• Consequence: TNFRSF14 NM_003820.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -1.25
• Publications: 27 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]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023900867).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0153 (2332/152350) while in subpopulation EAS AF = 0.0399 (207/5188). AF 95% confidence interval is 0.0355. There are 36 homozygotes in GnomAd4. There are 1091 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 36 AR gene

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.349G>A	p.Ala117Thr	missense	Exon 4 of 8	NP_003811.2
	TNFRSF14	NM_001297605.2		c.349G>A	p.Ala117Thr	missense	Exon 4 of 7	NP_001284534.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF14	ENST00000355716.5	TSL:1 MANE Select	c.349G>A	p.Ala117Thr	missense	Exon 4 of 8	ENSP00000347948.4
	TNFRSF14	ENST00000475523.5	TSL:1	n.586G>A		non_coding_transcript_exon	Exon 2 of 6
	TNFRSF14	ENST00000434817.5	TSL:3	c.349G>A	p.Ala117Thr	missense	Exon 5 of 7	ENSP00000415254.1

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2321 AN: 152232 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.0350

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00621

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0402

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00629

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0107 AC: 2503 AN: 233130 AF XY: 0.0102

Gnomad AFR exome AF: 0.0368

Gnomad AMR exome AF: 0.00355

Gnomad ASJ exome AF: 0.00175

Gnomad EAS exome AF: 0.0383

Gnomad FIN exome AF: 0.00232

Gnomad NFE exome AF: 0.00632

Gnomad OTH exome AF: 0.00890

GnomAD4 exome AF: 0.00817 AC: 11881 AN: 1453942 Hom.: 106 Cov.: 34 AF XY: 0.00819 AC XY: 5918 AN XY: 722526

African (AFR) AF: 0.0366 AC: 1222 AN: 33360

American (AMR) AF: 0.00408 AC: 179 AN: 43924

Ashkenazi Jewish (ASJ) AF: 0.00185 AC: 48 AN: 25960

East Asian (EAS) AF: 0.0275 AC: 1084 AN: 39398

South Asian (SAS) AF: 0.0150 AC: 1273 AN: 84802

European-Finnish (FIN) AF: 0.00254 AC: 131 AN: 51594

Middle Eastern (MID) AF: 0.00764 AC: 44 AN: 5762

European-Non Finnish (NFE) AF: 0.00659 AC: 7307 AN: 1109070

Other (OTH) AF: 0.00987 AC: 593 AN: 60072

GnomAD4 genome AF: 0.0153 AC: 2332 AN: 152350 Hom.: 36 Cov.: 33 AF XY: 0.0146 AC XY: 1091 AN XY: 74488

African (AFR) AF: 0.0352 AC: 1463 AN: 41582

American (AMR) AF: 0.00621 AC: 95 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.0399 AC: 207 AN: 5188

South Asian (SAS) AF: 0.0153 AC: 74 AN: 4830

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00629 AC: 428 AN: 68024

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.00929 Hom.: 15

Bravo AF: 0.0165

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.0339 AC: 149

ESP6500EA AF: 0.00641 AC: 55

ExAC AF: 0.0105 AC: 1266

Asia WGS AF: 0.0310 AC: 108 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.063
DANN	Benign	0.68
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0028	N
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-2.0	N
PhyloP100		-1.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	3.5	N
REVEL	Benign	0.20
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.80	P
Vest4		0.016
MPC		0.15
ClinPred		0.0090	T
GERP RS		0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.058
gMVP		0.61
Mutation Taster		=99/1	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: rs2234163; hg19: chr1-2491306; COSMIC: COSV104672684; COSMIC: COSV104672684;