Genetic Variant NM_015650.4:c.28C>A (chr2-238320690-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_015650.4(TRAF3IP1):c.28C>A(p.Gln10Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000158 in 1,269,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q10E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

TRAF3IP1
NM_015650.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.27

Publications

0 publications found

Variant links:

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]

TRAF3IP1 Gene-Disease associations (from GenCC):

Senior-Loken syndrome 9
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Senior-Loken syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
short rib-polydactyly syndrome, Majewski type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TRAF3IP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35727945).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRAF3IP1	NM_015650.4 link	c.28C>A	p.Gln10Lys	missense_variant	Exon 1 of 17	ENST00000373327.5	NP_056465.2	Q8TDR0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TRAF3IP1	ENST00000373327.5 link	c.28C>A	p.Gln10Lys	missense_variant	Exon 1 of 17	1	NM_015650.4	ENSP00000362424.4	Q8TDR0-1
TRAF3IP1	ENST00000391993.7 link	c.28C>A	p.Gln10Lys	missense_variant	Exon 1 of 15	1		ENSP00000375851.3	Q8TDR0-2
TRAF3IP1	ENST00000409739.2 link	n.28C>A		non_coding_transcript_exon_variant	Exon 1 of 5	3		ENSP00000386648.2	H7BZ10

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000158

AC:

AN:

1269224

Hom.:

Cov.:

AF XY:

0.00000160

AC XY:

AN XY:

625956

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

25598

American (AMR)

AF:

0.00

AC:

AN:

25278

Ashkenazi Jewish (ASJ)

AF:

0.0000479

AC:

AN:

20870

East Asian (EAS)

AF:

0.00

AC:

AN:

25468

South Asian (SAS)

AF:

0.00

AC:

AN:

67980

European-Finnish (FIN)

AF:

0.0000228

AC:

AN:

43890

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4780

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1005394

Other (OTH)

AF:

0.00

AC:

AN:

49966

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.070

.;T

Eigen

Benign

0.15

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.89

D;D

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.36

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

M;M

PhyloP100

6.3

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-2.6

D;D

REVEL

Benign

0.16

Sift

Benign

0.059

T;T

Sift4G

Benign

0.39

T;T

Polyphen

0.45

P;P

Vest4

0.57

MutPred

0.50

Gain of methylation at Q10 (P = 0.0326);Gain of methylation at Q10 (P = 0.0326);

MVP

0.38

MPC

0.19

ClinPred

0.95

GERP RS

3.4

PromoterAI

0.017

Neutral

(source)

Varity_R

0.75

gMVP

0.69

Mutation Taster

=45/55

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over