2-238320670-C-G

Position:

• chr2-238320670-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015650.4(TRAF3IP1):​c.8C>G​(p.Ala3Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000242 in 1,241,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: TRAF3IP1 NM_015650.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.395

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0752238).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRAF3IP1	NM_015650.4	c.8C>G	p.Ala3Gly	missense_variant	1/17	ENST00000373327.5	NP_056465.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRAF3IP1	ENST00000373327.5	c.8C>G	p.Ala3Gly	missense_variant	1/17	1	NM_015650.4	ENSP00000362424.4
TRAF3IP1	ENST00000391993.7	c.8C>G	p.Ala3Gly	missense_variant	1/15	1		ENSP00000375851.3
TRAF3IP1	ENST00000409739.2	n.8C>G		non_coding_transcript_exon_variant	1/5	3		ENSP00000386648.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000242 AC: 3 AN: 1241124 Hom.: 0 Cov.: 30 AF XY: 0.00000491 AC XY: 3 AN XY: 611382

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000202

Gnomad4 OTH exome AF: 0.0000207

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2019

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with TRAF3IP1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces alanine with glycine at codon 3 of the TRAF3IP1 protein (p.Ala3Gly). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and glycine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0079	.;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.075	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.44	N;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.027
Sift	Benign	0.34	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.0	B;B
Vest4		0.063
MutPred		0.27		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.23
MPC		0.14
ClinPred		0.17	T
GERP RS		2.4
Varity_R		0.099
gMVP		0.22

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: rs1697476086; hg19: chr2-239229311;