rs13190932

chr6-111591867-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_147686.4(TRAF3IP2):c.220C>T(p.Arg74Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0559 in 1,614,154 control chromosomes in the GnomAD database, including 2,724 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R74Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.050 (208 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2516 hom.)
• Consequence: TRAF3IP2 NM_147686.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.937

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018520057).
• BP6: Variant 6-111591867-G-A is Benign according to our data. Variant chr6-111591867-G-A is described in ClinVar as [Benign]. Clinvar id is 403566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0569 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAF3IP2	NM_147686.4	c.220C>T	p.Arg74Trp	missense_variant	2/9	ENST00000368761.11
TRAF3IP2-AS1	NR_034108.1	n.486-5971G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAF3IP2	ENST00000368761.11	c.220C>T	p.Arg74Trp	missense_variant	2/9	1	NM_147686.4	P4
TRAF3IP2-AS1	ENST00000687951.2	n.446-5971G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0497 AC: 7567 AN: 152154 Hom.: 210 Cov.: 32

Gnomad AFR AF: 0.0374

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.0483

Gnomad ASJ AF: 0.0888

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0369

Gnomad FIN AF: 0.0565

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0584

Gnomad OTH AF: 0.0583

GnomAD3 exomes AF: 0.0531 AC: 13359 AN: 251428 Hom.: 394 AF XY: 0.0535 AC XY: 7270 AN XY: 135882

Gnomad AFR exome AF: 0.0363

Gnomad AMR exome AF: 0.0598

Gnomad ASJ exome AF: 0.0949

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0463

Gnomad FIN exome AF: 0.0613

Gnomad NFE exome AF: 0.0582

Gnomad OTH exome AF: 0.0619

GnomAD4 exome AF: 0.0565 AC: 82586 AN: 1461882 Hom.: 2516 Cov.: 31 AF XY: 0.0565 AC XY: 41098 AN XY: 727246

Gnomad4 AFR exome AF: 0.0372

Gnomad4 AMR exome AF: 0.0599

Gnomad4 ASJ exome AF: 0.0962

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0475

Gnomad4 FIN exome AF: 0.0618

Gnomad4 NFE exome AF: 0.0585

Gnomad4 OTH exome AF: 0.0562

GnomAD4 genome AF: 0.0497 AC: 7570 AN: 152272 Hom.: 208 Cov.: 32 AF XY: 0.0482 AC XY: 3590 AN XY: 74448

Gnomad4 AFR AF: 0.0373

Gnomad4 AMR AF: 0.0483

Gnomad4 ASJ AF: 0.0888

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0375

Gnomad4 FIN AF: 0.0565

Gnomad4 NFE AF: 0.0584

Gnomad4 OTH AF: 0.0572

Alfa AF: 0.0578 Hom.: 602

Bravo AF: 0.0493

TwinsUK AF: 0.0547 AC: 203

ALSPAC AF: 0.0568 AC: 219

ESP6500AA AF: 0.0361 AC: 159

ESP6500EA AF: 0.0597 AC: 513

ExAC AF: 0.0509 AC: 6178

Asia WGS AF: 0.0210 AC: 75 AN: 3478

EpiCase AF: 0.0598

EpiControl AF: 0.0576

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

Candidiasis, familial, 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	12
Dann	Benign	0.77
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.74	T;T;.;T
MetaRNN	Benign	0.0019	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.16	T
PROVEAN	Benign	0.66	N;N;N;.
REVEL	Benign	0.025
Sift	Benign	0.052	T;T;T;.
Sift4G	Benign	0.10	T;T;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.086
MPC		0.20
ClinPred		0.0045	T
GERP RS		-5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.14

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: rs13190932; hg19: chr6-111913070; COSMIC: COSV60675422; COSMIC: COSV60675422;