16-11556585-G-C

Position:

• chr16-11556585-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_001136472.2(LITAF):​c.146C>G​(p.Thr49Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T49M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LITAF NM_001136472.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.74

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 4 ACMG points.

• PM1: In a chain Lipopolysaccharide-induced tumor necrosis factor-alpha factor (size 160) in uniprot entity LITAF_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_001136472.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-11556585-G-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.23876691).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LITAF	NM_001136472.2	c.146C>G	p.Thr49Arg	missense_variant	2/4	ENST00000622633.5	NP_001129944.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LITAF	ENST00000622633.5	c.146C>G	p.Thr49Arg	missense_variant	2/4	1	NM_001136472.2	ENSP00000483114.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	17
DANN	Benign	0.47
DEOGEN2	Benign	0.28	T;T;.;T;.;T;T;T;T;T;.;.;.;.;T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.84	.;T;.;.;T;.;T;.;.;T;T;T;T;T;T;T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.7	L;L;L;L;L;L;.;L;L;.;.;L;.;.;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.59	.;.;N;N;N;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.35
Sift	Benign	0.13	.;.;T;T;D;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.57	T;T;T;T;T;T;T;T;T;.;.;T;.;T;T;T
Polyphen		0.089	B;B;.;B;P;B;.;B;B;.;.;.;.;.;.;.
Vest4		0.50
MutPred		0.20		Loss of glycosylation at T49 (P = 0.0224);Loss of glycosylation at T49 (P = 0.0224);Loss of glycosylation at T49 (P = 0.0224);Loss of glycosylation at T49 (P = 0.0224);Loss of glycosylation at T49 (P = 0.0224);Loss of glycosylation at T49 (P = 0.0224);Loss of glycosylation at T49 (P = 0.0224);Loss of glycosylation at T49 (P = 0.0224);Loss of glycosylation at T49 (P = 0.0224);Loss of glycosylation at T49 (P = 0.0224);Loss of glycosylation at T49 (P = 0.0224);Loss of glycosylation at T49 (P = 0.0224);Loss of glycosylation at T49 (P = 0.0224);Loss of glycosylation at T49 (P = 0.0224);Loss of glycosylation at T49 (P = 0.0224);.;
MVP		0.97
MPC		0.18
ClinPred		0.31	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.078
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs141862602; hg19: chr16-11650441;