rs104894521

chr16-11553564-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_001136472.2(LITAF):c.346T>G(p.Trp116Gly) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W116C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LITAF NM_001136472.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 6.70

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001136472.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• PP5: Variant 16-11553564-A-C is Pathogenic according to our data. Variant chr16-11553564-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 6059.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-11553564-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LITAF	NM_001136472.2	c.346T>G	p.Trp116Gly	missense_variant	3/4	ENST00000622633.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LITAF	ENST00000622633.5	c.346T>G	p.Trp116Gly	missense_variant	3/4	1	NM_001136472.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00209 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 14, 2003	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LITAF function (PMID: 21896645, 23166352, 23359569, 23576546, 25058650). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 6059). This variant is also known as SIMPLE p.Trp116Gly. This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 12525712, 15122712, 28211240). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 116 of the LITAF protein (p.Trp116Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	32
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.96	D;D;.;D;.;D;.;D;D;D;.;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	2.9	M;M;M;M;M;M;.;M;M;.;.;M;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.70	T
Sift4G	Pathogenic	0.0010	D;D;T;D;D;D;D;D;D;.;.;T;.;T
Polyphen		1.0	D;D;.;D;.;D;.;D;D;.;.;.;.;.
Vest4		0.93
MutPred		0.77		Loss of catalytic residue at L114 (P = 0.0543);Loss of catalytic residue at L114 (P = 0.0543);Loss of catalytic residue at L114 (P = 0.0543);Loss of catalytic residue at L114 (P = 0.0543);Loss of catalytic residue at L114 (P = 0.0543);Loss of catalytic residue at L114 (P = 0.0543);.;Loss of catalytic residue at L114 (P = 0.0543);Loss of catalytic residue at L114 (P = 0.0543);Loss of catalytic residue at L114 (P = 0.0543);Loss of catalytic residue at L114 (P = 0.0543);Loss of catalytic residue at L114 (P = 0.0543);Loss of catalytic residue at L114 (P = 0.0543);Loss of catalytic residue at L114 (P = 0.0543);
MVP		0.99
MPC		0.88
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs104894521; hg19: chr16-11647420;