rs61756667

Variant names:

• chr6-111591806-C-T
• rs61756667
• NM_147686.4:c.281G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000368761.11(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. 15/22 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 ENST00000368761.11 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.56
• Publications: 6 publications found

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

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 541100.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 = 0.00109 (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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000368761.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAF3IP2	NM_147686.4	MANE Select	c.281G>A	p.Ser94Asn	missense	Exon 2 of 9	NP_679211.2
	TRAF3IP2	NM_147200.3		c.308G>A	p.Ser103Asn	missense	Exon 3 of 10	NP_671733.2
	TRAF3IP2	NM_001164281.3		c.281G>A	p.Ser94Asn	missense	Exon 2 of 9	NP_001157753.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAF3IP2	ENST00000368761.11	TSL:1 MANE Select	c.281G>A	p.Ser94Asn	missense	Exon 2 of 9	ENSP00000357750.5
	TRAF3IP2	ENST00000340026.10	TSL:1	c.308G>A	p.Ser103Asn	missense	Exon 3 of 10	ENSP00000345984.6
	TRAF3IP2	ENST00000528599.1	TSL:1	n.476G>A		non_coding_transcript_exon	Exon 2 of 5

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

GnomAD2 exomes AF: 0.00156 AC: 392 AN: 251446 AF XY: 0.00171

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 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

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.00107 AC: 48 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0123 AC: 322 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00307 AC: 265 AN: 86258

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53418

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00104 AC: 1154 AN: 1112012

Other (OTH) AF: 0.00199 AC: 120 AN: 60396

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

African (AFR) AF: 0.000120 AC: 5 AN: 41590

American (AMR) AF: 0.000588 AC: 9 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0132 AC: 46 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4832

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00138 AC: 94 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00152 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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Candidiasis, familial, 8 (1)
-	-	1	Psoriasis 13, susceptibility to;C3714992:Candidiasis, familial, 8 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.6
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.093
Sift	Uncertain	0.023	D
Sift4G	Benign	0.18	T
Polyphen		0.53	P
Vest4		0.29
MVP		0.53
MPC		0.36
ClinPred		0.0087	T
GERP RS		5.0
Varity_R		0.12
gMVP		0.31
Mutation Taster		=296/4	polymorphism

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

Other links and lift over

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