rs104894520

Positions:

• chr16-11553566-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_001136472.2(LITAF):​c.344C>A​(p.Thr115Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LITAF NM_001136472.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.18

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885
• PP5: Variant 16-11553566-G-T is Pathogenic according to our data. Variant chr16-11553566-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-11553566-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LITAF	NM_001136472.2	c.344C>A	p.Thr115Asn	missense_variant	3/4	ENST00000622633.5	NP_001129944.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LITAF	ENST00000622633.5	c.344C>A	p.Thr115Asn	missense_variant	3/4	1	NM_001136472.2	ENSP00000483114.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 1C Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 14, 2003	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 17, 2021	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been reported to affect LITAF protein function (PMID: 23576546, 25058650, 25963657). This variant has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 12525712, Invitae). ClinVar contains an entry for this variant (Variation ID: 6058). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with asparagine at codon 115 of the LITAF protein (p.Thr115Asn). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and asparagine. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 07, 2018	Not found in the total gnomAD dataset, and the data is high quality (0/282336 chr). Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Very strong co-segregation with disease in affected and unaffected individuals, but from a single family. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2024	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect on exosome production (PMID: 23576546); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25963657, 25058650, 12525712, 23576546) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;D;.;D;.;D;.;D;D;D;.;.;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	.;D;.;.;D;.;D;.;.;D;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.2	M;M;M;M;M;M;.;M;M;.;.;M;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.7	.;.;D;D;D;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	.;.;D;D;D;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D;D;.;.;D;.;D
Polyphen		0.99	D;D;.;D;.;D;.;D;D;.;.;.;.;.
Vest4		0.86
MutPred		0.77		Gain of catalytic residue at T115 (P = 0.0478);Gain of catalytic residue at T115 (P = 0.0478);Gain of catalytic residue at T115 (P = 0.0478);Gain of catalytic residue at T115 (P = 0.0478);Gain of catalytic residue at T115 (P = 0.0478);Gain of catalytic residue at T115 (P = 0.0478);.;Gain of catalytic residue at T115 (P = 0.0478);Gain of catalytic residue at T115 (P = 0.0478);Gain of catalytic residue at T115 (P = 0.0478);Gain of catalytic residue at T115 (P = 0.0478);Gain of catalytic residue at T115 (P = 0.0478);Gain of catalytic residue at T115 (P = 0.0478);Gain of catalytic residue at T115 (P = 0.0478);
MVP		1.0
MPC		0.67
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.76
gMVP		0.87

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: rs104894520; hg19: chr16-11647422;