3-49829477-C-T

Position:

chr3-49829477-C-T

Variant summary

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

The NM_005879.3(TRAIP):c.1268G>A(p.Arg423Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R423R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

TRAIP
NM_005879.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.96

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 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
TRAIP	NM_005879.3 linkuse as main transcript	c.1268G>A	p.Arg423Gln	missense_variant	14/15	ENST00000331456.7
TRAIP	XM_017005526.2 linkuse as main transcript	c.971G>A	p.Arg324Gln	missense_variant	11/12
TRAIP	XM_047447240.1 linkuse as main transcript	c.740G>A	p.Arg247Gln	missense_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
TRAIP	ENST00000331456.7 linkuse as main transcript	c.1268G>A	p.Arg423Gln	missense_variant	14/15	1	NM_005879.3	P1
TRAIP	ENST00000469027.5 linkuse as main transcript	c.803G>A	p.Arg268Gln	missense_variant	9/9	5
TRAIP	ENST00000491060.1 linkuse as main transcript	n.190G>A		non_coding_transcript_exon_variant	2/2	3
TRAIP	ENST00000473195.5 linkuse as main transcript	c.*441G>A		3_prime_UTR_variant, NMD_transcript_variant	9/10	3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251408

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Feb 24, 2023

ClinVar contains an entry for this variant (Variation ID: 1943576). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 423 of the TRAIP protein (p.Arg423Gln). This variant is present in population databases (rs142854364, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with TRAIP-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬† is likely to be tolerated. 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

Benign

0.15

BayesDel_addAF

Uncertain

0.085

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.23

T;T

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.031

MetaRNN

Uncertain

0.49

T;T

MetaSVM

Uncertain

-0.032

MutationAssessor

Uncertain

2.7

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.81

N;N

REVEL

Benign

0.20

Sift

Uncertain

0.018

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.68

MVP

0.85

MPC

0.59

ClinPred

0.93

GERP RS

5.3

Varity_R

0.25

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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