rs149860754

Variant names:

• chr6-111591396-G-A
• rs149860754
• NM_147686.4:c.691C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-111591396-G-A
• chr6-111591396-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BS1_Supporting

The NM_147686.4(TRAF3IP2):​c.691C>T​(p.Leu231Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00031 in 1,549,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L231V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: TRAF3IP2 NM_147686.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.65
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.4100241).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00025 (38/152188) while in subpopulation NFE AF = 0.000558 (38/68040). AF 95% confidence interval is 0.000418. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.691C>T	p.Leu231Phe	missense	Exon 2 of 9	NP_679211.2	O43734-2
	TRAF3IP2	NM_147200.3		c.718C>T	p.Leu240Phe	missense	Exon 3 of 10	NP_671733.2	O43734-1
	TRAF3IP2	NM_001164281.3		c.691C>T	p.Leu231Phe	missense	Exon 2 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.691C>T	p.Leu231Phe	missense	Exon 2 of 9	ENSP00000357750.5	O43734-2
	TRAF3IP2	ENST00000340026.10	TSL:1	c.718C>T	p.Leu240Phe	missense	Exon 3 of 10	ENSP00000345984.6	O43734-1
	TRAF3IP2	ENST00000528599.1	TSL:1	n.886C>T		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000558

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000293 AC: 58 AN: 197744 AF XY: 0.000256

Gnomad AFR exome AF: 0.000128

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000585

Gnomad OTH exome AF: 0.000219

GnomAD4 exome AF: 0.000316 AC: 442 AN: 1397172 Hom.: 0 Cov.: 31 AF XY: 0.000303 AC XY: 209 AN XY: 689158

African (AFR) AF: 0.000128 AC: 4 AN: 31132

American (AMR) AF: 0.00 AC: 0 AN: 33402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21360

East Asian (EAS) AF: 0.00 AC: 0 AN: 39206

South Asian (SAS) AF: 0.00 AC: 0 AN: 75720

European-Finnish (FIN) AF: 0.0000785 AC: 4 AN: 50948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5422

European-Non Finnish (NFE) AF: 0.000391 AC: 423 AN: 1082546

Other (OTH) AF: 0.000192 AC: 11 AN: 57436

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000558 AC: 38 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000384 Hom.: 0

Bravo AF: 0.000253

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000363 AC: 44

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.7
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.68
MVP		0.67
MPC		0.79
ClinPred		0.15	T
GERP RS		5.8
Varity_R		0.20
gMVP		0.21
Mutation Taster		=70/30	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: rs149860754; hg19: chr6-111912599;