Genetic Variant TNFRSF14:c.304+606C>G (chr1-2559074-C-G) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

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

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: -2.00

Publications

2 publications found

Variant links:

COSMIC-nc: COSV63187909

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF14	NM_003820.4 link	c.304+606C>G		intron_variant	Intron 3 of 7	ENST00000355716.5	NP_003811.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF14	ENST00000355716.5 link	c.304+606C>G		intron_variant	Intron 3 of 7	1	NM_003820.4	ENSP00000347948.4

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1580

AN:

152216

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.000981

AC XY:

583

AN XY:

594314

show subpopulations

African (AFR)

AF:

0.0383

AC:

1081

AN:

28226

American (AMR)

AF:

0.00248

AC:

AN:

30658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21016

East Asian (EAS)

AF:

0.00

AC:

AN:

24100

South Asian (SAS)

AF:

0.0000911

AC:

AN:

76824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

12782

Middle Eastern (MID)

AF:

0.000818

AC:

AN:

4888

European-Non Finnish (NFE)

AF:

0.0000340

AC:

AN:

969984

Other (OTH)

AF:

0.00295

AC:

142

AN:

48178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

183

275

366

458

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0104

AC:

1586

AN:

152334

Hom.:

Cov.:

AF XY:

0.00985

AC XY:

734

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.0356

AC:

1480

AN:

41570

American (AMR)

AF:

0.00503

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68028

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

154

230

307

384

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000560

Hom.:

Bravo

AF:

0.0116

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.99

CADD

Benign

0.36

(source)

DANN

Benign

0.45

PhyloP100

-2.0

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over