rs61742338

Positions:

• chr2-238328747-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000373327.5(TRAF3IP1):​c.416G>A​(p.Arg139Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0339 in 1,613,950 control chromosomes in the GnomAD database, including 1,053 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R139W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.024 (58 hom., cov: 32)
  • Exomes 𝑓: 0.035 (995 hom.)
• Consequence: TRAF3IP1 ENST00000373327.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.43

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001930654).
• BP6: Variant 2-238328747-G-A is Benign according to our data. Variant chr2-238328747-G-A is described in ClinVar as [Benign]. Clinvar id is 1167927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0238 (3618/152108) while in subpopulation NFE AF= 0.0374 (2542/67996). AF 95% confidence interval is 0.0362. There are 58 homozygotes in gnomad4. There are 1646 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 58 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRAF3IP1	NM_015650.4	c.416G>A	p.Arg139Gln	missense_variant	4/17	ENST00000373327.5	NP_056465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRAF3IP1	ENST00000373327.5	c.416G>A	p.Arg139Gln	missense_variant	4/17	1	NM_015650.4	ENSP00000362424
TRAF3IP1	ENST00000391993.7	c.416G>A	p.Arg139Gln	missense_variant	4/15	1		ENSP00000375851	P1
TRAF3IP1	ENST00000409739.2	c.*285G>A		3_prime_UTR_variant, NMD_transcript_variant	4/5	3		ENSP00000386648

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3619 AN: 151990 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.00687

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0201

Gnomad ASJ AF: 0.0377

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0245

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0374

Gnomad OTH AF: 0.0249

GnomAD3 exomes AF: 0.0260 AC: 6525 AN: 251372 Hom.: 110 AF XY: 0.0265 AC XY: 3596 AN XY: 135850

Gnomad AFR exome AF: 0.00665

Gnomad AMR exome AF: 0.0165

Gnomad ASJ exome AF: 0.0373

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0270

Gnomad FIN exome AF: 0.0160

Gnomad NFE exome AF: 0.0363

Gnomad OTH exome AF: 0.0285

GnomAD4 exome AF: 0.0349 AC: 51046 AN: 1461842 Hom.: 995 Cov.: 31 AF XY: 0.0348 AC XY: 25284 AN XY: 727226

Gnomad4 AFR exome AF: 0.00559

Gnomad4 AMR exome AF: 0.0173

Gnomad4 ASJ exome AF: 0.0368

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0265

Gnomad4 FIN exome AF: 0.0156

Gnomad4 NFE exome AF: 0.0394

Gnomad4 OTH exome AF: 0.0324

GnomAD4 genome AF: 0.0238 AC: 3618 AN: 152108 Hom.: 58 Cov.: 32 AF XY: 0.0221 AC XY: 1646 AN XY: 74342

Gnomad4 AFR AF: 0.00685

Gnomad4 AMR AF: 0.0200

Gnomad4 ASJ AF: 0.0377

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0251

Gnomad4 FIN AF: 0.0148

Gnomad4 NFE AF: 0.0374

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0342 Hom.: 168

Bravo AF: 0.0237

TwinsUK AF: 0.0399 AC: 148

ALSPAC AF: 0.0410 AC: 158

ESP6500AA AF: 0.00840 AC: 37

ESP6500EA AF: 0.0399 AC: 343

ExAC AF: 0.0249 AC: 3028

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

TRAF3IP1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 26, 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	0.094
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0097	.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.091
Sift	Benign	0.062	T;T
Sift4G	Uncertain	0.030	D;D
Polyphen		0.086	B;B
Vest4		0.15
MPC		0.39
ClinPred		0.018	T
GERP RS		0.17
Varity_R		0.030
gMVP		0.16

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

Publications

LitVar

Other links and lift over

dbSNP: rs61742338; hg19: chr2-239237388;