6-111580250-G-T

Variant names:

• chr6-111580250-G-T
• rs1043730
• NM_147686.4:c.969C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_147686.4(TRAF3IP2):​c.969C>A​(p.His323Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.806 in 1,614,006 control chromosomes in the GnomAD database, including 528,557 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. H323H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.85 (56204 hom., cov: 34)
  • Exomes 𝑓: 0.80 (472353 hom.)
• Consequence: TRAF3IP2 NM_147686.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.260
• Publications: 43 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=5.539725E-7).
• BP6: Variant 6-111580250-G-T is Benign according to our data. Variant chr6-111580250-G-T is described in ClinVar as Benign. ClinVar VariationId is 403565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAF3IP2	NM_147686.4	MANE Select	c.969C>A	p.His323Gln	missense	Exon 3 of 9	NP_679211.2
	TRAF3IP2	NM_147200.3		c.996C>A	p.His332Gln	missense	Exon 4 of 10	NP_671733.2
	TRAF3IP2	NM_001164281.3		c.969C>A	p.His323Gln	missense	Exon 3 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.969C>A	p.His323Gln	missense	Exon 3 of 9	ENSP00000357750.5
	TRAF3IP2	ENST00000340026.10	TSL:1	c.996C>A	p.His332Gln	missense	Exon 4 of 10	ENSP00000345984.6
	TRAF3IP2	ENST00000528599.1	TSL:1	n.1164C>A		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes AF: 0.855 AC: 130068 AN: 152180 Hom.: 56133 Cov.: 34

Gnomad AFR AF: 0.961

Gnomad AMI AF: 0.860

Gnomad AMR AF: 0.857

Gnomad ASJ AF: 0.777

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.936

Gnomad FIN AF: 0.854

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.778

Gnomad OTH AF: 0.840

GnomAD2 exomes AF: 0.852 AC: 213609 AN: 250782 AF XY: 0.849

Gnomad AFR exome AF: 0.966

Gnomad AMR exome AF: 0.902

Gnomad ASJ exome AF: 0.783

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.844

Gnomad NFE exome AF: 0.783

Gnomad OTH exome AF: 0.819

GnomAD4 exome AF: 0.801 AC: 1171133 AN: 1461708 Hom.: 472353 Cov.: 66 AF XY: 0.805 AC XY: 585086 AN XY: 727160

African (AFR) AF: 0.966 AC: 32347 AN: 33476

American (AMR) AF: 0.899 AC: 40191 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 20448 AN: 26134

East Asian (EAS) AF: 1.00 AC: 39686 AN: 39696

South Asian (SAS) AF: 0.934 AC: 80542 AN: 86254

European-Finnish (FIN) AF: 0.840 AC: 44857 AN: 53418

Middle Eastern (MID) AF: 0.798 AC: 4599 AN: 5764

European-Non Finnish (NFE) AF: 0.773 AC: 859550 AN: 1111884

Other (OTH) AF: 0.810 AC: 48913 AN: 60376

GnomAD4 genome AF: 0.855 AC: 130199 AN: 152298 Hom.: 56204 Cov.: 34 AF XY: 0.860 AC XY: 64056 AN XY: 74468

African (AFR) AF: 0.961 AC: 39971 AN: 41576

American (AMR) AF: 0.857 AC: 13114 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.777 AC: 2698 AN: 3472

East Asian (EAS) AF: 0.998 AC: 5174 AN: 5182

South Asian (SAS) AF: 0.936 AC: 4515 AN: 4824

European-Finnish (FIN) AF: 0.854 AC: 9051 AN: 10604

Middle Eastern (MID) AF: 0.765 AC: 225 AN: 294

European-Non Finnish (NFE) AF: 0.778 AC: 52887 AN: 68016

Other (OTH) AF: 0.842 AC: 1780 AN: 2114

Alfa AF: 0.803 Hom.: 190321

Bravo AF: 0.858

ESP6500AA AF: 0.959 AC: 4224

ESP6500EA AF: 0.778 AC: 6695

ExAC AF: 0.853 AC: 103599

Asia WGS AF: 0.964 AC: 3352 AN: 3478

EpiCase AF: 0.765

EpiControl AF: 0.772

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: Frequency

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 100% of patients studied by a panel of primary immunodeficiencies. Number of patients: 95. Only high quality variants are reported.

Candidiasis, familial, 8 Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	9.6
DANN	Benign	0.82
DEOGEN2	Benign	0.027	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.080	T
MetaRNN	Benign	5.5e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.5	N
PhyloP100		0.26
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.65	N
REVEL	Benign	0.060
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.043
MutPred		0.17		Gain of relative solvent accessibility (P = 0.0999)
MPC		0.19
ClinPred		0.0024	T
GERP RS		3.5
Varity_R		0.036
gMVP		0.089
Mutation Taster		=298/2	polymorphism (auto)

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: rs1043730; hg19: chr6-111901453; COSMIC: COSV107416209; COSMIC: COSV107416209;