2-238329110-A-G

Position:

• chr2-238329110-A-G

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.683A>G​(p.Asn228Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0601 in 1,550,390 control chromosomes in the GnomAD database, including 5,130 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 (1737 hom., cov: 31)
  • Exomes 𝑓: 0.054 (3393 hom.)
• Consequence: TRAF3IP1 NM_015650.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.658

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=0.0046848953).
• BP6: Variant 2-238329110-A-G is Benign according to our data. Variant chr2-238329110-A-G is described in ClinVar as [Benign]. Clinvar id is 1167549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRAF3IP1	NM_015650.4	c.683A>G	p.Asn228Ser	missense_variant	5/17	ENST00000373327.5	NP_056465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRAF3IP1	ENST00000373327.5	c.683A>G	p.Asn228Ser	missense_variant	5/17	1	NM_015650.4	ENSP00000362424
TRAF3IP1	ENST00000391993.7	c.683A>G	p.Asn228Ser	missense_variant	5/15	1		ENSP00000375851	P1
TRAF3IP1	ENST00000409739.2	c.*552A>G		3_prime_UTR_variant, NMD_transcript_variant	5/5	3		ENSP00000386648

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17578 AN: 151526 Hom.: 1732 Cov.: 31

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0814

Gnomad ASJ AF: 0.0473

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0394

Gnomad OTH AF: 0.0982

GnomAD3 exomes AF: 0.0810 AC: 12466 AN: 153818 Hom.: 778 AF XY: 0.0782 AC XY: 6330 AN XY: 80904

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.0759

Gnomad ASJ exome AF: 0.0467

Gnomad EAS exome AF: 0.108

Gnomad SAS exome AF: 0.101

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.0409

Gnomad OTH exome AF: 0.0702

GnomAD4 exome AF: 0.0541 AC: 75608 AN: 1398746 Hom.: 3393 Cov.: 31 AF XY: 0.0546 AC XY: 37684 AN XY: 690062

Gnomad4 AFR exome AF: 0.280

Gnomad4 AMR exome AF: 0.0768

Gnomad4 ASJ exome AF: 0.0451

Gnomad4 EAS exome AF: 0.112

Gnomad4 SAS exome AF: 0.0985

Gnomad4 FIN exome AF: 0.103

Gnomad4 NFE exome AF: 0.0386

Gnomad4 OTH exome AF: 0.0673

GnomAD4 genome AF: 0.116 AC: 17609 AN: 151644 Hom.: 1737 Cov.: 31 AF XY: 0.118 AC XY: 8773 AN XY: 74120

Gnomad4 AFR AF: 0.267

Gnomad4 AMR AF: 0.0815

Gnomad4 ASJ AF: 0.0473

Gnomad4 EAS AF: 0.102

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.113

Gnomad4 NFE AF: 0.0394

Gnomad4 OTH AF: 0.0972

Alfa AF: 0.0570 Hom.: 692

Bravo AF: 0.120

TwinsUK AF: 0.0345 AC: 128

ALSPAC AF: 0.0418 AC: 161

ESP6500AA AF: 0.234 AC: 975

ESP6500EA AF: 0.0362 AC: 298

ExAC AF: 0.0443 AC: 3961

Asia WGS AF: 0.0980 AC: 341 AN: 3478

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	0.053
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.2
DANN	Benign	0.24
DEOGEN2	Benign	0.0048	.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.15	T;T
MetaRNN	Benign	0.0047	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.60	N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.060	N;N
REVEL	Benign	0.033
Sift	Benign	0.42	T;T
Sift4G	Benign	0.86	T;T
Polyphen		0.0	B;B
Vest4		0.026
MPC		0.11
ClinPred		0.0012	T
GERP RS		-0.82
Varity_R		0.013
gMVP		0.026

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: rs3769110; hg19: chr2-239237751;