rs146226365

chr6-111580262-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_147686.4(TRAF3IP2):c.957C>A(p.Ser319Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,613,054 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (10 hom.)
• Consequence: TRAF3IP2 NM_147686.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.252

Genes affected

TRAF3IP2 (HGNC:1343): (TRAF3 interacting protein 2) This gene encodes a protein involved in regulating responses to cytokines by members of the Rel/NF-kappaB transcription factor family. These factors play a central role in innate immunity in response to pathogens, inflammatory signals and stress. This gene product interacts with TRAF proteins (tumor necrosis factor receptor-associated factors) and either I-kappaB kinase or MAP kinase to activate either NF-kappaB or Jun kinase. Several alternative transcripts encoding different isoforms have been identified. Another transcript, which does not encode a protein and is transcribed in the opposite orientation, has been identified. Overexpression of this transcript has been shown to reduce expression of at least one of the protein encoding transcripts, suggesting it has a regulatory role in the expression of this gene. [provided by RefSeq, Aug 2009]

TRAF3IP2-AS1 (HGNC:40005): (TRAF3IP2 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007829368).
• BP6: Variant 6-111580262-G-T is Benign according to our data. Variant chr6-111580262-G-T is described in ClinVar as [Benign]. Clinvar id is 541101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00118 (179/152336) while in subpopulation SAS AF= 0.00518 (25/4828). AF 95% confidence interval is 0.0036. There are 1 homozygotes in gnomad4. There are 87 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAF3IP2	NM_147686.4	c.957C>A	p.Ser319Arg	missense_variant	3/9	ENST00000368761.11
TRAF3IP2-AS1	NR_034108.1	n.485+3792G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAF3IP2	ENST00000368761.11	c.957C>A	p.Ser319Arg	missense_variant	3/9	1	NM_147686.4	P4
TRAF3IP2-AS1	ENST00000687951.2	n.445+3792G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 152218 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00177 AC: 445 AN: 250766 Hom.: 1 AF XY: 0.00191 AC XY: 259 AN XY: 135526

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.0159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00363

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00122

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00131 AC: 1912 AN: 1460718 Hom.: 10 Cov.: 34 AF XY: 0.00144 AC XY: 1048 AN XY: 726692

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.0169

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00413

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.000806

Gnomad4 OTH exome AF: 0.00230

GnomAD4 genome AF: 0.00118 AC: 179 AN: 152336 Hom.: 1 Cov.: 33 AF XY: 0.00117 AC XY: 87 AN XY: 74490

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00115

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00160 Hom.: 0

Bravo AF: 0.00108

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00182 AC: 221

EpiCase AF: 0.00213

EpiControl AF: 0.00213

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Candidiasis, familial, 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

TRAF3IP2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Benign	0.14
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.62	T;T;.;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0078	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.3	N;N;N;.
REVEL	Benign	0.11
Sift	Uncertain	0.010	D;D;D;.
Sift4G	Uncertain	0.044	D;D;D;D
Polyphen		0.94	P;.;P;P
Vest4		0.27
MutPred		0.37		.;.;Gain of MoRF binding (P = 0.0245);Gain of MoRF binding (P = 0.0245);
MVP		0.56
MPC		0.25
ClinPred		0.051	T
GERP RS		1.8
Varity_R		0.066
gMVP		0.38

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: rs146226365; hg19: chr6-111901465;