rs767809270

Positions:

• chr16-11556646-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BS1_Supporting BS2

The NM_001136472.2(LITAF):​c.85G>A​(p.Val29Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: LITAF NM_001136472.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.663

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 Benign. Variant got -7 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.066491425).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000144 (21/1461888) while in subpopulation MID AF= 0.000173 (1/5768). AF 95% confidence interval is 0.0000117. There are 0 homozygotes in gnomad4_exome. There are 10 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LITAF	NM_001136472.2	c.85G>A	p.Val29Ile	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.85G>A	p.Val29Ile	missense_variant	2/4	1	NM_001136472.2	ENSP00000483114.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000108 Hom.: 0

Bravo AF: 0.00000756

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 532704). This variant has not been reported in the literature in individuals affected with LITAF-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 29 of the LITAF protein (p.Val29Ile). -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2020

The p.V29I variant (also known as c.85G>A), located in coding exon 1 of the LITAF gene, results from a G to A substitution at nucleotide position 85. The valine at codon 29 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	0.0041	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	11
DANN	Benign	0.84
DEOGEN2	Benign	0.18	T;T;.;T;.;T;T;T;T;T;.;.;.;.;T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.79	.;T;.;.;T;.;T;.;.;T;T;T;T;T;T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.066	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.81	L;L;L;L;L;L;.;L;L;.;.;L;.;.;.;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.28	.;.;N;N;N;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.18
Sift	Benign	0.28	.;.;T;T;T;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.61	T;T;T;T;T;T;T;T;T;.;.;T;.;T;T;T;.
Polyphen		0.0	B;B;.;B;B;B;.;B;B;.;.;.;.;.;.;.;.
Vest4		0.18
MutPred		0.26		Loss of catalytic residue at V29 (P = 0.0045);Loss of catalytic residue at V29 (P = 0.0045);Loss of catalytic residue at V29 (P = 0.0045);Loss of catalytic residue at V29 (P = 0.0045);Loss of catalytic residue at V29 (P = 0.0045);Loss of catalytic residue at V29 (P = 0.0045);Loss of catalytic residue at V29 (P = 0.0045);Loss of catalytic residue at V29 (P = 0.0045);Loss of catalytic residue at V29 (P = 0.0045);Loss of catalytic residue at V29 (P = 0.0045);Loss of catalytic residue at V29 (P = 0.0045);Loss of catalytic residue at V29 (P = 0.0045);Loss of catalytic residue at V29 (P = 0.0045);Loss of catalytic residue at V29 (P = 0.0045);Loss of catalytic residue at V29 (P = 0.0045);.;Loss of catalytic residue at V29 (P = 0.0045);
MVP		0.43
MPC		0.12
ClinPred		0.059	T
GERP RS		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs767809270; hg19: chr16-11650502;