Variant 17-28744254-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000262395.10(TRAF4):c.142A>G(p.Ser48Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000018 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TRAF4
ENST00000262395.10 missense, splice_region

Scores

Splicing: ADA: 0.9997

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.99

Variant links:

Genes affected

TRAF4 (HGNC:12034): (TNF receptor associated factor 4) This gene encodes a member of the TNF receptor associated factor (TRAF) family. TRAF proteins are associated with, and mediate signal transduction from members of the TNF receptor superfamily. The encoded protein has been shown to interact with neurotrophin receptor, p75 (NTR/NTSR1), and negatively regulate NTR induced cell death and NF-kappa B activation. This protein has been found to bind to p47phox, a cytosolic regulatory factor included in a multi-protein complex known as NAD(P)H oxidase. This protein thus, is thought to be involved in the oxidative activation of MAPK8/JNK. Alternatively spliced transcript variants have been observed but the full-length nature of only one has been determined. [provided by RefSeq, Jul 2008]

TRAF4 links:

TRAF4 (HGNC:):

TRAF4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRAF4	NM_004295.4 linkuse as main transcript	c.142A>G	p.Ser48Gly	missense_variant, splice_region_variant	1/7	ENST00000262395.10	NP_004286.2	Q9BUZ4-1A0A024QZ59
TRAF4	XM_011525504.4 linkuse as main transcript	c.142A>G	p.Ser48Gly	missense_variant, splice_region_variant	1/7		XP_011523806.1	A0A024QZ19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRAF4	ENST00000262395.10 linkuse as main transcript	c.142A>G	p.Ser48Gly	missense_variant, splice_region_variant	1/7	1	NM_004295.4	ENSP00000262395.5		Q9BUZ4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000459

AC:

AN:

217780

Hom.:

AF XY:

0.00000823

AC XY:

AN XY:

121436

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000348

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000176

AC:

AN:

1133500

Hom.:

Cov.:

AF XY:

0.00000354

AC XY:

AN XY:

564492

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000247

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2022

The c.142A>G (p.S48G) alteration is located in exon 1 (coding exon 1) of the TRAF4 gene. This alteration results from a A to G substitution at nucleotide position 142, causing the serine (S) at amino acid position 48 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

DANN

Benign

0.88

DEOGEN2

Uncertain

0.42

T;.;T;T;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.79

T;T;T;T;T

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.38

T;T;T;T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

-0.13

N;.;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.0

N;.;N;N;N

REVEL

Benign

0.29

Sift

Benign

0.58

T;.;T;T;T

Sift4G

Benign

0.39

T;T;T;T;T

Polyphen

0.010

B;.;.;.;.

Vest4

0.41

MutPred

0.50

Loss of catalytic residue at S48 (P = 0.0432);Loss of catalytic residue at S48 (P = 0.0432);Loss of catalytic residue at S48 (P = 0.0432);Loss of catalytic residue at S48 (P = 0.0432);Loss of catalytic residue at S48 (P = 0.0432);

MVP

0.76

MPC

0.64

ClinPred

0.23

GERP RS

3.9

Varity_R

0.31

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.34

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over