Genetic Variant TNFRSF14:p.Pro11Thr (chr1-2556695-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_003820.4(TNFRSF14):c.31C>A(p.Pro11Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P11S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TNFRSF14
NM_003820.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.02

Publications

0 publications found

Variant links:

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:

TNFRSF14-AS1 (HGNC:26966): (TNFRSF14 antisense RNA 1)

TNFRSF14-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32164454).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TNFRSF14	NM_003820.4	MANE Select	c.31C>A	p.Pro11Thr	missense	Exon 1 of 8	NP_003811.2
TNFRSF14	NM_001297605.2		c.31C>A	p.Pro11Thr	missense	Exon 1 of 7	NP_001284534.1
TNFRSF14-AS1	NR_037844.2		n.37G>T		splice_region non_coding_transcript_exon	Exon 2 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TNFRSF14	ENST00000355716.5	TSL:1 MANE Select	c.31C>A	p.Pro11Thr	missense	Exon 1 of 8	ENSP00000347948.4	Q92956-1
TNFRSF14	ENST00000475523.5	TSL:1	n.70+240C>A		intron	N/A
TNFRSF14	ENST00000860787.1		c.31C>A	p.Pro11Thr	missense	Exon 1 of 8	ENSP00000530846.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1456300

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724078

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33274

American (AMR)

AF:

0.00

AC:

AN:

44156

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25778

East Asian (EAS)

AF:

0.00

AC:

AN:

39640

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85340

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52884

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109412

Other (OTH)

AF:

0.00

AC:

AN:

60072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

0.0028

BayesDel_noAF

Benign

-0.23

CADD

Benign

5.7

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.028

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.044

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.32

MetaSVM

Uncertain

-0.23

MutationAssessor

Uncertain

2.2

PhyloP100

-2.0

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.36

Sift

Uncertain

0.010

Sift4G

Pathogenic

0.0

Polyphen

0.41

Vest4

0.22

MutPred

0.45

Gain of phosphorylation at P11 (P = 0.0078)

MVP

0.72

MPC

0.56

ClinPred

0.44

GERP RS

0.38

PromoterAI

-0.12

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.069

gMVP

0.31

Mutation Taster

=94/6

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over