rs104894521

Variant names:

• chr16-11553564-A-C
• rs104894521
• NM_001136472.2:c.346T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 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
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease type 1C

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• Charcot-Marie-Tooth disease

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 VariationId is 6059.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LITAF	NM_001136472.2	c.346T>G	p.Trp116Gly	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.346T>G	p.Trp116Gly	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

Alfa AF: 0.000548 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

Jan 14, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
LIST_S2	Uncertain	0.88	.;D;.;.;D;.;D;.;.;D;D;D;D;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;.;.
PhyloP100		6.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-12	.;.;D;D;D;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	.;.;D;D;D;.;.;.;.;.;.;.;.;.
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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894521; hg19: chr16-11647420;