rs146226365

Variant names:

• chr6-111580262-G-T
• rs146226365
• NM_147686.4:c.957C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-111580262-G-T
• chr6-111580262-G-A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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. 14/22 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, single submitter B:2
• Conservation: PhyloP100: 0.252
• Publications: 5 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 -14 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 VariationId is 541101.Status of the report is criteria_provided_single_submitter, 1 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_147686.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAF3IP2	NM_147686.4	MANE Select	c.957C>A	p.Ser319Arg	missense	Exon 3 of 9	NP_679211.2	O43734-2
	TRAF3IP2	NM_147200.3		c.984C>A	p.Ser328Arg	missense	Exon 4 of 10	NP_671733.2	O43734-1
	TRAF3IP2	NM_001164281.3		c.957C>A	p.Ser319Arg	missense	Exon 3 of 9	NP_001157753.1	O43734-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAF3IP2	ENST00000368761.11	TSL:1 MANE Select	c.957C>A	p.Ser319Arg	missense	Exon 3 of 9	ENSP00000357750.5	O43734-2
	TRAF3IP2	ENST00000340026.10	TSL:1	c.984C>A	p.Ser328Arg	missense	Exon 4 of 10	ENSP00000345984.6	O43734-1
	TRAF3IP2	ENST00000528599.1	TSL:1	n.1152C>A		non_coding_transcript_exon	Exon 3 of 5

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

GnomAD2 exomes AF: 0.00177 AC: 445 AN: 250766 AF XY: 0.00191

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 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

African (AFR) AF: 0.0000598 AC: 2 AN: 33434

American (AMR) AF: 0.000425 AC: 19 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0169 AC: 441 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00413 AC: 356 AN: 86230

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53408

Middle Eastern (MID) AF: 0.00868 AC: 50 AN: 5762

European-Non Finnish (NFE) AF: 0.000806 AC: 895 AN: 1111036

Other (OTH) AF: 0.00230 AC: 139 AN: 60358

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

African (AFR) AF: 0.0000962 AC: 4 AN: 41580

American (AMR) AF: 0.000457 AC: 7 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00115 AC: 78 AN: 68034

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00153 Hom.: 1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Candidiasis, familial, 8 (1)
-	-	1	TRAF3IP2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.25
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.11
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.044	D
Polyphen		0.94	P
Vest4		0.27
MutPred		0.37		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
Mutation Taster		=92/8	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: rs146226365; hg19: chr6-111901465;