16-11553566-G-T

Variant names:

• chr16-11553566-G-T
• rs104894520
• NM_001136472.2:c.344C>A

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]

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 rank	MANE	Protein	UniProt
LITAF	NM_001136472.2	c.344C>A	p.Thr115Asn	missense_variant	Exon 3 of 4	ENST00000622633.5	NP_001129944.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LITAF	ENST00000622633.5	c.344C>A	p.Thr115Asn	missense_variant	Exon 3 of 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

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 17, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported to affect LITAF protein function (PMID: 23576546, 25058650, 25963657). 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. This variant is not present in population databases (ExAC no frequency). 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). 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. -

Jan 14, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Nov 07, 2018

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 01, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;