chr1-211369465-A-T

Position:

chr1-211369465-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001033910.3(TRAF5):c.803A>T(p.His268Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000516 in 1,590,492 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H268Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

TRAF5
NM_001033910.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.35

Variant links:

Genes affected

TRAF5 (HGNC:12035): (TNF receptor associated factor 5) The scaffold protein encoded by this gene is a member of the tumor necrosis factor receptor-associated factor (TRAF) protein family and contains a meprin and TRAF homology (MATH) domain, a RING-type zinc finger, and two TRAF-type zinc fingers. TRAF proteins are associated with, and mediate signal transduction from members of the TNF receptor superfamily. This protein is one of the components of a multiple protein complex which binds to tumor necrosis factor (TNF) receptor cytoplasmic domains and mediates TNF-induced activation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

TRAF5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.034230888).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRAF5	NM_001033910.3 linkuse as main transcript	c.803A>T	p.His268Leu	missense_variant	9/11	ENST00000261464.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRAF5	ENST00000261464.10 linkuse as main transcript	c.803A>T	p.His268Leu	missense_variant	9/11	1	NM_001033910.3	P1	O00463-1
TRAF5	ENST00000367004.3 linkuse as main transcript	c.803A>T	p.His268Leu	missense_variant	9/11	1		P1	O00463-1
TRAF5	ENST00000336184.6 linkuse as main transcript	c.803A>T	p.His268Leu	missense_variant	9/11	5		P1	O00463-1
TRAF5	ENST00000473385.1 linkuse as main transcript	n.537A>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000780

AC:

AN:

230908

Hom.:

AF XY:

0.000120

AC XY:

AN XY:

124894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000657

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000466

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000521

AC:

AN:

1438174

Hom.:

Cov.:

AF XY:

0.0000685

AC XY:

AN XY:

714852

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000673

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000647

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.05e-7

Gnomad4 OTH exome

AF:

0.0000674

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000901

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.000123

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2021

The c.803A>T (p.H268L) alteration is located in exon 9 (coding exon 8) of the TRAF5 gene. This alteration results from a A to T substitution at nucleotide position 803, causing the histidine (H) at amino acid position 268 to be replaced by a leucine (L). 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

Benign

0.11

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.61

DEOGEN2

Benign

0.090

T;T;T

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.55

T;.;.

M_CAP

Benign

0.014

MetaRNN

Benign

0.034

T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.2

L;L;L

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.029

Sift

Benign

0.098

T;T;T

Sift4G

Benign

0.55

T;T;T

Polyphen

0.0010

B;B;B

Vest4

0.37

MutPred

0.31

Loss of catalytic residue at L267 (P = 0.2137);Loss of catalytic residue at L267 (P = 0.2137);Loss of catalytic residue at L267 (P = 0.2137);

MVP

0.31

MPC

0.16

ClinPred

0.020

GERP RS

3.1

Varity_R

0.10

gMVP

0.52

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over