2-238397627-A-C

Position:

• chr2-238397627-A-C

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.1858A>C​(p.Met620Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0759 in 1,607,770 control chromosomes in the GnomAD database, including 5,344 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 ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M620I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.062 (386 hom., cov: 32)
  • Exomes 𝑓: 0.077 (4958 hom.)
• Consequence: TRAF3IP1 NM_015650.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.126

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=0.0017504692).
• BP6: Variant 2-238397627-A-C is Benign according to our data. Variant chr2-238397627-A-C is described in ClinVar as [Benign]. Clinvar id is 1166906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0788 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAF3IP1	NM_015650.4	c.1858A>C	p.Met620Leu	missense_variant	16/17	ENST00000373327.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAF3IP1	ENST00000373327.5	c.1858A>C	p.Met620Leu	missense_variant	16/17	1	NM_015650.4
TRAF3IP1	ENST00000391993.7	c.1660A>C	p.Met554Leu	missense_variant	14/15	1		P1
TRAF3IP1	ENST00000462122.1	n.869A>C		non_coding_transcript_exon_variant	7/7	3
TRAF3IP1	ENST00000483951.1	n.206A>C		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.0615 AC: 9313 AN: 151342 Hom.: 384 Cov.: 32

Gnomad AFR AF: 0.0237

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.0416

Gnomad ASJ AF: 0.0479

Gnomad EAS AF: 0.0457

Gnomad SAS AF: 0.0453

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0805

Gnomad OTH AF: 0.0551

GnomAD3 exomes AF: 0.0635 AC: 15763 AN: 248156 Hom.: 714 AF XY: 0.0645 AC XY: 8687 AN XY: 134602

Gnomad AFR exome AF: 0.0198

Gnomad AMR exome AF: 0.0262

Gnomad ASJ exome AF: 0.0415

Gnomad EAS exome AF: 0.0385

Gnomad SAS exome AF: 0.0397

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.0790

Gnomad OTH exome AF: 0.0617

GnomAD4 exome AF: 0.0774 AC: 112720 AN: 1456310 Hom.: 4958 Cov.: 33 AF XY: 0.0763 AC XY: 55314 AN XY: 724508

Gnomad4 AFR exome AF: 0.0212

Gnomad4 AMR exome AF: 0.0306

Gnomad4 ASJ exome AF: 0.0503

Gnomad4 EAS exome AF: 0.0321

Gnomad4 SAS exome AF: 0.0422

Gnomad4 FIN exome AF: 0.147

Gnomad4 NFE exome AF: 0.0835

Gnomad4 OTH exome AF: 0.0688

GnomAD4 genome AF: 0.0615 AC: 9322 AN: 151460 Hom.: 386 Cov.: 32 AF XY: 0.0625 AC XY: 4626 AN XY: 74008

Gnomad4 AFR AF: 0.0238

Gnomad4 AMR AF: 0.0416

Gnomad4 ASJ AF: 0.0479

Gnomad4 EAS AF: 0.0456

Gnomad4 SAS AF: 0.0455

Gnomad4 FIN AF: 0.141

Gnomad4 NFE AF: 0.0806

Gnomad4 OTH AF: 0.0560

Alfa AF: 0.0686 Hom.: 756

Bravo AF: 0.0528

TwinsUK AF: 0.0928 AC: 344

ALSPAC AF: 0.0867 AC: 334

ESP6500AA AF: 0.0234 AC: 103

ESP6500EA AF: 0.0776 AC: 667

ExAC AF: 0.0667 AC: 8093

Asia WGS AF: 0.0370 AC: 127 AN: 3418

EpiCase AF: 0.0712

EpiControl AF: 0.0733

ClinVar

Significance: Benign

Submissions summary: Benign:3

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	This variant is associated with the following publications: (PMID: 21835309) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	16
DANN	Benign	0.58
DEOGEN2	Benign	0.0070	.;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.25	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.8	.;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.49	N;N
REVEL	Benign	0.052
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.098
MutPred		0.61		.;Loss of catalytic residue at M620 (P = 0.0267);
MPC		0.13
ClinPred		0.00022	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.038
gMVP		0.048

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: rs3739070; hg19: chr2-239306268; COSMIC: COSV64852869;