rs61756667

Positions:

• chr6-111591806-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_147686.4(TRAF3IP2):​c.281G>A​(p.Ser94Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,614,266 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (4 hom.)
• Consequence: TRAF3IP2 NM_147686.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.56

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=0.005608052).
• BP6: Variant 6-111591806-C-T is Benign according to our data. Variant chr6-111591806-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 541100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-111591806-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00109 (166/152374) while in subpopulation SAS AF= 0.00186 (9/4832). AF 95% confidence interval is 0.00115. There are 0 homozygotes in gnomad4. There are 69 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAF3IP2	NM_147686.4	c.281G>A	p.Ser94Asn	missense_variant	2/9	ENST00000368761.11
TRAF3IP2-AS1	NR_034108.1	n.486-6032C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAF3IP2	ENST00000368761.11	c.281G>A	p.Ser94Asn	missense_variant	2/9	1	NM_147686.4	P4
TRAF3IP2-AS1	ENST00000687951.2	n.446-6032C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152256 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.0132

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00156 AC: 392 AN: 251446 Hom.: 2 AF XY: 0.00171 AC XY: 232 AN XY: 135898

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00274

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00123

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00132 AC: 1924 AN: 1461892 Hom.: 4 Cov.: 31 AF XY: 0.00141 AC XY: 1027 AN XY: 727248

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.0123

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00307

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00104

Gnomad4 OTH exome AF: 0.00199

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152374 Hom.: 0 Cov.: 32 AF XY: 0.000926 AC XY: 69 AN XY: 74520

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.0132

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00138

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00161 Hom.: 0

Bravo AF: 0.000975

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00143 AC: 174

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.00178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	TRAF3IP2: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Candidiasis, familial, 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Psoriasis 13, susceptibility to;C3714992:Candidiasis, familial, 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Jun 27, 2022

This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF: 1.3% [130/10368], including in 2 homozygotes; https://gnomad.broadinstitute.org/variant/6-111913009-C-T?dataset=gnomad_r2_1 ), and in ClinVar, with multiple laboratories classifying it as benign (Variation ID: 541100). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	.;.;T;T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.80	T;T;.;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0056	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	.;.;L;L
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.79	N;N;N;.
REVEL	Benign	0.093
Sift	Uncertain	0.023	D;D;D;.
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.53	P;.;B;B
Vest4		0.29
MVP		0.53
MPC		0.36
ClinPred		0.0087	T
GERP RS		5.0
Varity_R		0.12
gMVP		0.31

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: rs61756667; hg19: chr6-111913009; COSMIC: COSV99056458; COSMIC: COSV99056458;