16-11553684-C-T

Position:

chr16-11553684-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM1BP4BP6BS1BS2

The NM_001136472.2(LITAF):c.226G>A(p.Val76Met) variant causes a missense change. The variant allele was found at a frequency of 0.000108 in 1,613,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

LITAF
NM_001136472.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 5.69

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:

LITAF (HGNC:):

LITAF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM1

In a domain LITAF (size 84) in uniprot entity LITAF_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_001136472.2

BP4

Computational evidence support a benign effect (MetaRNN=0.27432743).

BP6

Variant 16-11553684-C-T is Benign according to our data. Variant chr16-11553684-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 464048.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000191 (29/152084) while in subpopulation AFR AF= 0.000338 (14/41398). AF 95% confidence interval is 0.000204. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LITAF	NM_001136472.2 linkuse as main transcript	c.226G>A	p.Val76Met	missense_variant	3/4	ENST00000622633.5	NP_001129944.1	Q99732-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LITAF	ENST00000622633.5 linkuse as main transcript	c.226G>A	p.Val76Met	missense_variant	3/4	1	NM_001136472.2	ENSP00000483114.1		Q99732-1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000116

AC:

AN:

250756

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135560

show subpopulations

Gnomad AFR exome

AF:

0.000494

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000999

AC:

146

AN:

1461780

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000962

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000191

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.000338

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000263

Hom.:

Bravo

AF:

0.000242

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 1C

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 76 of the LITAF protein (p.Val76Met). This variant is present in population databases (rs371334679, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 25614874). ClinVar contains an entry for this variant (Variation ID: 464048). 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 tolerated. 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

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2017

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

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

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.81

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

M_CAP

Uncertain

0.098

MetaRNN

Benign

0.27

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

MetaSVM

Uncertain

0.22

MutationAssessor

Benign

1.6

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

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.1

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

REVEL

Uncertain

0.47

Sift

Benign

0.070

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

Sift4G

Uncertain

0.046

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

Polyphen

0.82

P;P;.;P;.;P;P;P;.;.;.;.;.

Vest4

0.68

MVP

0.94

MPC

0.23

ClinPred

0.056

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.054

gMVP

0.68

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