rs58277463

Positions:

• chr2-238344583-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015650.4(TRAF3IP1):​c.1246A>T​(p.Thr416Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0604 in 1,613,720 control chromosomes in the GnomAD database, including 5,390 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.12 (1766 hom., cov: 32)
  • Exomes 𝑓: 0.055 (3624 hom.)
• Consequence: TRAF3IP1 NM_015650.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.401

Genes affected

TRAF3IP1 (HGNC:17861): (TRAF3 interacting protein 1) The protein encoded by this gene interacts with TNF receptor-associated factor 3, tethering it to cytoskeletal microtubules. The encoded protein is also an inhibitor of the innate type I IFN response. Defects in this gene are a cause of Senior-Loken syndrome 9. [provided by RefSeq, Mar 2017]

TRAF3IP1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004148662).
• BP6: Variant 2-238344583-A-T is Benign according to our data. Variant chr2-238344583-A-T is described in ClinVar as [Benign]. Clinvar id is 1167552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRAF3IP1	NM_015650.4	c.1246A>T	p.Thr416Ser	missense_variant	9/17	ENST00000373327.5	NP_056465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRAF3IP1	ENST00000373327.5	c.1246A>T	p.Thr416Ser	missense_variant	9/17	1	NM_015650.4	ENSP00000362424.4
TRAF3IP1	ENST00000391993.7	c.1064-2872A>T		intron_variant		1		ENSP00000375851.3

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17732 AN: 152060 Hom.: 1761 Cov.: 32

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0818

Gnomad ASJ AF: 0.0472

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0393

Gnomad OTH AF: 0.0981

GnomAD3 exomes AF: 0.0787 AC: 19793 AN: 251456 Hom.: 1269 AF XY: 0.0752 AC XY: 10226 AN XY: 135914

Gnomad AFR exome AF: 0.269

Gnomad AMR exome AF: 0.0752

Gnomad ASJ exome AF: 0.0457

Gnomad EAS exome AF: 0.110

Gnomad SAS exome AF: 0.0998

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.0402

Gnomad OTH exome AF: 0.0738

GnomAD4 exome AF: 0.0545 AC: 79698 AN: 1461542 Hom.: 3624 Cov.: 31 AF XY: 0.0550 AC XY: 40014 AN XY: 727082

Gnomad4 AFR exome AF: 0.279

Gnomad4 AMR exome AF: 0.0769

Gnomad4 ASJ exome AF: 0.0448

Gnomad4 EAS exome AF: 0.112

Gnomad4 SAS exome AF: 0.0984

Gnomad4 FIN exome AF: 0.103

Gnomad4 NFE exome AF: 0.0384

Gnomad4 OTH exome AF: 0.0667

GnomAD4 genome AF: 0.117 AC: 17764 AN: 152178 Hom.: 1766 Cov.: 32 AF XY: 0.119 AC XY: 8856 AN XY: 74404

Gnomad4 AFR AF: 0.268

Gnomad4 AMR AF: 0.0819

Gnomad4 ASJ AF: 0.0472

Gnomad4 EAS AF: 0.103

Gnomad4 SAS AF: 0.114

Gnomad4 FIN AF: 0.114

Gnomad4 NFE AF: 0.0393

Gnomad4 OTH AF: 0.0971

Alfa AF: 0.0514 Hom.: 286

Bravo AF: 0.120

TwinsUK AF: 0.0345 AC: 128

ALSPAC AF: 0.0418 AC: 161

ESP6500AA AF: 0.255 AC: 1124

ESP6500EA AF: 0.0395 AC: 340

ExAC AF: 0.0806 AC: 9787

Asia WGS AF: 0.0980 AC: 340 AN: 3478

EpiCase AF: 0.0423

EpiControl AF: 0.0449

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

TRAF3IP1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.5
DANN	Benign	0.52
DEOGEN2	Benign	0.0055	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.028
Sift	Benign	0.20	T
Sift4G	Benign	0.48	T
Polyphen		0.011	B
Vest4		0.062
MPC		0.14
ClinPred		0.00071	T
GERP RS		3.1
Varity_R		0.041
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs58277463; hg19: chr2-239253224; COSMIC: COSV64852074; COSMIC: COSV64852074;