3-49829461-C-A

Position:

chr3-49829461-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000331456.7(TRAIP):c.1284G>T(p.Gln428His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000738 in 1,613,978 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00077 ( 2 hom. )

Consequence

TRAIP
ENST00000331456.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.175

Variant links:

Genes affected

TRAIP (HGNC:30764): (TRAF interacting protein) This gene encodes a protein that contains an N-terminal RING finger motif and a putative coiled-coil domain. A similar murine protein interacts with TNFR-associated factor 1 (TRAF1), TNFR-associated factor 2 (TRAF2), and cylindromatosis. The interaction with TRAF2 inhibits TRAF2-mediated nuclear factor kappa-B, subunit 1 activation that is required for cell activation and protection against apoptosis. [provided by RefSeq, Jul 2008]

TRAIP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13700587).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TRAIP	NM_005879.3 linkuse as main transcript	c.1284G>T	p.Gln428His	missense_variant	14/15	ENST00000331456.7	NP_005870.2
TRAIP	XM_017005526.2 linkuse as main transcript	c.987G>T	p.Gln329His	missense_variant	11/12		XP_016861015.1
TRAIP	XM_047447240.1 linkuse as main transcript	c.756G>T	p.Gln252His	missense_variant	9/10		XP_047303196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
TRAIP	ENST00000331456.7 linkuse as main transcript	c.1284G>T	p.Gln428His	missense_variant	14/15	1	NM_005879.3	ENSP00000328203	P1
TRAIP	ENST00000469027.5 linkuse as main transcript	c.819G>T	p.Gln273His	missense_variant	9/9	5		ENSP00000420085
TRAIP	ENST00000491060.1 linkuse as main transcript	n.206G>T		non_coding_transcript_exon_variant	2/2	3
TRAIP	ENST00000473195.5 linkuse as main transcript	c.*457G>T		3_prime_UTR_variant, NMD_transcript_variant	9/10	3		ENSP00000419556

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000616

AC:

155

AN:

251422

Hom.:

AF XY:

0.000626

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000324

Gnomad NFE exome

AF:

0.00120

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000770

AC:

1125

AN:

1461856

Hom.:

Cov.:

AF XY:

0.000733

AC XY:

533

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000206

Gnomad4 NFE exome

AF:

0.000960

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.000434

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.000431

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000735

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000777

Hom.:

Bravo

AF:

0.000465

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000923

AC:

112

EpiCase

AF:

0.000436

EpiControl

AF:

0.00113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 12, 2022

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 428 of the TRAIP protein (p.Gln428His). This variant is present in population databases (rs146306196, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TRAIP-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;T

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.7

M;.

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.24

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;.

Vest4

0.70

MutPred

0.23

Loss of ubiquitination at K425 (P = 0.0683);.;

MVP

0.76

MPC

1.0

ClinPred

0.077

GERP RS

0.72

Varity_R

0.27

gMVP

0.79

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

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