1-2559459-C-A

Variant names:

• chr1-2559459-C-A
• rs2257763
• ENST00000475523.5:n.178C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000475523.5(TNFRSF14):​n.178C>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 1,414,678 control chromosomes in the GnomAD database, including 189,792 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.58 (26210 hom., cov: 32)
  • Exomes 𝑓: 0.51 (163582 hom.)
• Consequence: TNFRSF14 ENST00000475523.5 non_coding_transcript_exon
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.0550
• Publications: 18 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.748 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000475523.5. 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.305-364C>A		intron	N/A	NP_003811.2
	TNFRSF14	NM_001297605.2		c.305-364C>A		intron	N/A	NP_001284534.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF14	ENST00000475523.5	TSL:1	n.178C>A		non_coding_transcript_exon	Exon 2 of 6
	TNFRSF14	ENST00000355716.5	TSL:1 MANE Select	c.305-364C>A		intron	N/A	ENSP00000347948.4
	TNFRSF14	ENST00000463471.6	TSL:2	n.1389C>A		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes AF: 0.576 AC: 87219 AN: 151398 Hom.: 26162 Cov.: 32

Gnomad AFR AF: 0.755

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.563

Gnomad ASJ AF: 0.457

Gnomad EAS AF: 0.539

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.507

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.490

Gnomad OTH AF: 0.550

GnomAD2 exomes AF: 0.541 AC: 72790 AN: 134530 AF XY: 0.544

Gnomad AFR exome AF: 0.771

Gnomad AMR exome AF: 0.540

Gnomad ASJ exome AF: 0.456

Gnomad EAS exome AF: 0.539

Gnomad FIN exome AF: 0.486

Gnomad NFE exome AF: 0.487

Gnomad OTH exome AF: 0.518

GnomAD4 exome AF: 0.509 AC: 642565 AN: 1263168 Hom.: 163582 Cov.: 62 AF XY: 0.512 AC XY: 317071 AN XY: 618694

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.764 AC: 22605 AN: 29596

American (AMR) AF: 0.538 AC: 17271 AN: 32086

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 10397 AN: 22456

East Asian (EAS) AF: 0.521 AC: 13797 AN: 26498

South Asian (SAS) AF: 0.642 AC: 49562 AN: 77210

European-Finnish (FIN) AF: 0.484 AC: 9116 AN: 18840

Middle Eastern (MID) AF: 0.556 AC: 2864 AN: 5154

European-Non Finnish (NFE) AF: 0.490 AC: 489946 AN: 1000022

Other (OTH) AF: 0.526 AC: 27007 AN: 51306

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.576 AC: 87317 AN: 151510 Hom.: 26210 Cov.: 32 AF XY: 0.578 AC XY: 42775 AN XY: 74054

African (AFR) AF: 0.755 AC: 31208 AN: 41332

American (AMR) AF: 0.562 AC: 8579 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 1581 AN: 3456

East Asian (EAS) AF: 0.537 AC: 2742 AN: 5102

South Asian (SAS) AF: 0.656 AC: 3130 AN: 4768

European-Finnish (FIN) AF: 0.507 AC: 5297 AN: 10456

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.489 AC: 33205 AN: 67838

Other (OTH) AF: 0.554 AC: 1164 AN: 2102

Alfa AF: 0.517 Hom.: 9831

Bravo AF: 0.580

Asia WGS AF: 0.678 AC: 2361 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
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.88
DANN	Benign	0.34
PhyloP100		-0.055
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2257763; hg19: chr1-2490898; COSMIC: COSV63187619; COSMIC: COSV63187619;