16-11549705-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BS1_SupportingBS2

The NM_001136472.2(LITAF):c.418G>A(p.Ala140Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,476 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A140P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

LITAF
NM_001136472.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.75

Variant links:

Genes affected

LITAF (HGNC:16841): (lipopolysaccharide induced TNF factor) Lipopolysaccharide is a potent stimulator of monocytes and macrophages, causing secretion of tumor necrosis factor-alpha (TNF-alpha) and other inflammatory mediators. This gene encodes lipopolysaccharide-induced TNF-alpha factor, which is a DNA-binding protein and can mediate the TNF-alpha expression by direct binding to the promoter region of the TNF-alpha gene. The transcription of this gene is induced by tumor suppressor p53 and has been implicated in the p53-induced apoptotic pathway. Mutations in this gene cause Charcot-Marie-Tooth disease type 1C (CMT1C) and may be involved in the carcinogenesis of extramammary Paget's disease (EMPD). Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2014]

LITAF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a domain LITAF (size 84) in uniprot entity LITAF_HUMAN there are 18 pathogenic changes around while only 6 benign (75%) in NM_001136472.2

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000116 (17/1461476) while in subpopulation NFE AF= 0.0000153 (17/1111844). AF 95% confidence interval is 0.00000931. There are 0 homozygotes in gnomad4_exome. There are 12 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LITAF	NM_001136472.2 link	c.418G>A	p.Ala140Thr	missense_variant	Exon 4 of 4	ENST00000622633.5	NP_001129944.1	Q99732-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LITAF	ENST00000622633.5 link	c.418G>A	p.Ala140Thr	missense_variant	Exon 4 of 4	1	NM_001136472.2	ENSP00000483114.1		Q99732-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250198

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

135332

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461476

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726990

show subpopulations

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:

0.0000153

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 1C

Uncertain:1

Aug 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 140 of the LITAF protein (p.Ala140Thr). This variant is present in population databases (rs754821950, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with LITAF-related conditions. ClinVar contains an entry for this variant (Variation ID: 576085). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

not provided

Uncertain:1

May 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.030

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.60

D;D;D;D;.;D;D;T

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.91

.;D;.;.;D;.;.;D

M_CAP

Uncertain

0.24

MetaRNN

Uncertain

0.48

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.036

MutationAssessor

Benign

1.4

L;L;L;L;.;L;L;.

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.7

.;.;N;.;.;.;.;.

REVEL

Uncertain

0.51

Sift

Benign

0.040

.;.;D;.;.;.;.;.

Sift4G

Benign

0.17

T;T;T;T;T;T;T;.

Polyphen

0.96

D;D;D;D;.;D;D;.

Vest4

0.48

MutPred

0.54

Loss of catalytic residue at A140 (P = 0.0625);Loss of catalytic residue at A140 (P = 0.0625);Loss of catalytic residue at A140 (P = 0.0625);Loss of catalytic residue at A140 (P = 0.0625);.;Loss of catalytic residue at A140 (P = 0.0625);Loss of catalytic residue at A140 (P = 0.0625);Loss of catalytic residue at A140 (P = 0.0625);

MVP

1.0

MPC

0.56

ClinPred

0.71

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.38

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