chr1-2559074-C-G

Variant names:

• chr1-2559074-C-G
• rs11573976
• NM_003820.4:c.304+606C>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_003820.4(TNFRSF14):​c.304+606C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,368,990 control chromosomes in the GnomAD database, including 42 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 0.010 (18 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (24 hom.)
• Consequence: TNFRSF14 NM_003820.4 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -2.00
• Publications: 2 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.08).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0104 (1586/152334) while in subpopulation AFR AF = 0.0356 (1480/41570). AF 95% confidence interval is 0.0341. There are 18 homozygotes in GnomAd4. There are 734 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 18 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.304+606C>G		intron	N/A	NP_003811.2
	TNFRSF14	NM_001297605.2		c.304+606C>G		intron	N/A	NP_001284534.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF14	ENST00000355716.5	TSL:1 MANE Select	c.304+606C>G		intron	N/A	ENSP00000347948.4
	TNFRSF14	ENST00000475523.5	TSL:1	n.71-278C>G		intron	N/A
	TNFRSF14	ENST00000442392.6	TSL:2	n.758C>G		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1580 AN: 152216 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.0355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00232 AC: 303 AN: 130366 AF XY: 0.00200

Gnomad AFR exome AF: 0.0371

Gnomad AMR exome AF: 0.00259

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000607

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.00110 AC: 1343 AN: 1216656 Hom.: 24 Cov.: 30 AF XY: 0.000981 AC XY: 583 AN XY: 594314

African (AFR) AF: 0.0383 AC: 1081 AN: 28226

American (AMR) AF: 0.00248 AC: 76 AN: 30658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21016

East Asian (EAS) AF: 0.00 AC: 0 AN: 24100

South Asian (SAS) AF: 0.0000911 AC: 7 AN: 76824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12782

Middle Eastern (MID) AF: 0.000818 AC: 4 AN: 4888

European-Non Finnish (NFE) AF: 0.0000340 AC: 33 AN: 969984

Other (OTH) AF: 0.00295 AC: 142 AN: 48178

GnomAD4 genome AF: 0.0104 AC: 1586 AN: 152334 Hom.: 18 Cov.: 33 AF XY: 0.00985 AC XY: 734 AN XY: 74494

African (AFR) AF: 0.0356 AC: 1480 AN: 41570

American (AMR) AF: 0.00503 AC: 77 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68028

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.000560 Hom.: 2

Bravo AF: 0.0116

Asia WGS AF: 0.00144 AC: 5 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	-0.99
CADD	Benign	0.36
DANN	Benign	0.45
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism

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: rs11573976; hg19: chr1-2490513; COSMIC: COSV63187909;