3-49829461-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005879.3(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 NM_005879.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.175

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13700587).

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152122 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000626 AC XY: 85 AN XY: 135878

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.: 2 Cov.: 32 AF XY: 0.000733 AC XY: 533 AN XY: 727234

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: 66 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.000431 AC XY: 32 AN XY: 74308

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.: 0

Bravo AF: 0.000465

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

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

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

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	T
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.46	T
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	T
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

Other links and lift over

dbSNP: rs146306196; hg19: chr3-49866894;