1-209775703-G-C

Position:

• chr1-209775703-G-C

Variant summary

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

The NM_025228.4(TRAF3IP3):​c.1020G>C​(p.Glu340Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRAF3IP3 NM_025228.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.06

Genes affected

TRAF3IP3 (HGNC:30766): (TRAF3 interacting protein 3) The gene encodes a protein that mediates cell growth by modulating the c-Jun N-terminal kinase signal transduction pathway. The encoded protein may also interact with a large multi-protein assembly containing the phosphatase 2A catalytic subunit. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

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=0.22751814).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAF3IP3	NM_025228.4	c.1020G>C	p.Glu340Asp	missense_variant	11/17	ENST00000367025.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAF3IP3	ENST00000367025.8	c.1020G>C	p.Glu340Asp	missense_variant	11/17	1	NM_025228.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.1020G>C (p.E340D) alteration is located in exon 11 (coding exon 9) of the TRAF3IP3 gene. This alteration results from a G to C substitution at nucleotide position 1020, causing the glutamic acid (E) at amino acid position 340 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T;T;.;T;T;T;T
Eigen	Benign	-0.021
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.87	D;.;D;D;D;D;D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.0	.;M;.;M;.;.;.
MutationTaster	Benign	0.80	N;N;N;N;N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.22	T;T;T;T;T;T;T
Sift4G	Benign	0.54	T;T;T;T;T;T;T
Polyphen		0.99	D;P;P;P;.;.;.
Vest4		0.34
MutPred		0.15		.;Gain of MoRF binding (P = 0.1828);.;Gain of MoRF binding (P = 0.1828);.;.;.;
MVP		0.77
MPC		0.32
ClinPred		0.80	D
GERP RS		1.7
Varity_R		0.072
gMVP		0.10

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: rs377426065; hg19: chr1-209949048;