16-11553546-G-C

Position:

• chr16-11553546-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_001136472.2(LITAF):​c.364C>G​(p.Leu122Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L122L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LITAF NM_001136472.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.48

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001136472.2
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-11553546-G-C is Pathogenic according to our data. Variant chr16-11553546-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 6060.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-11553546-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LITAF	NM_001136472.2	c.364C>G	p.Leu122Val	missense_variant	3/4	ENST00000622633.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LITAF	ENST00000622633.5	c.364C>G	p.Leu122Val	missense_variant	3/4	1	NM_001136472.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;D;.;D;.;D;.;D;D;D;.;.;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	.;D;.;.;D;.;D;.;.;D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.4	M;M;M;M;M;M;.;M;M;.;.;M;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.8	.;.;N;N;N;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	.;.;D;D;D;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.013	D;D;D;D;D;D;T;D;D;.;.;D;.;D
Polyphen		1.0	D;D;.;D;.;D;.;D;D;.;.;.;.;.
Vest4		0.79
MutPred		0.56		Gain of loop (P = 0.069);Gain of loop (P = 0.069);Gain of loop (P = 0.069);Gain of loop (P = 0.069);Gain of loop (P = 0.069);Gain of loop (P = 0.069);.;Gain of loop (P = 0.069);Gain of loop (P = 0.069);Gain of loop (P = 0.069);Gain of loop (P = 0.069);Gain of loop (P = 0.069);Gain of loop (P = 0.069);Gain of loop (P = 0.069);
MVP		1.0
MPC		0.65
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.48
gMVP		0.67

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: rs104894522; hg19: chr16-11647402;