rs4280262

chr16-11553636-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001136472.2(LITAF):c.274A>G(p.Ile92Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 1,613,820 control chromosomes in the GnomAD database, including 33,324 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2260 hom., cov: 31)
  • Exomes 𝑓: 0.20 (31064 hom.)
• Consequence: LITAF NM_001136472.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:9
• Conservation: PhyloP100: 0.370

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 -18 ACMG points.

• PM1: In a domain LITAF (size 84) in uniprot entity LITAF_HUMAN there are 18 pathogenic changes around while only 6 benign (75%) in NM_001136472.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0026205182).
• BP6: Variant 16-11553636-T-C is Benign according to our data. Variant chr16-11553636-T-C is described in ClinVar as [Benign]. Clinvar id is 317782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-11553636-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LITAF	NM_001136472.2	c.274A>G	p.Ile92Val	missense_variant	3/4	ENST00000622633.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LITAF	ENST00000622633.5	c.274A>G	p.Ile92Val	missense_variant	3/4	1	NM_001136472.2	P1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23901 AN: 151960 Hom.: 2259 Cov.: 31

Gnomad AFR AF: 0.0674

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.0675

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.150

GnomAD3 exomes AF: 0.166 AC: 41592 AN: 250932 Hom.: 4051 AF XY: 0.167 AC XY: 22714 AN XY: 135608

Gnomad AFR exome AF: 0.0624

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.0648

Gnomad SAS exome AF: 0.102

Gnomad FIN exome AF: 0.213

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.179

GnomAD4 exome AF: 0.200 AC: 292273 AN: 1461742 Hom.: 31064 Cov.: 34 AF XY: 0.198 AC XY: 143685 AN XY: 727160

Gnomad4 AFR exome AF: 0.0587

Gnomad4 AMR exome AF: 0.137

Gnomad4 ASJ exome AF: 0.159

Gnomad4 EAS exome AF: 0.0673

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.209

Gnomad4 NFE exome AF: 0.221

Gnomad4 OTH exome AF: 0.176

GnomAD4 genome AF: 0.157 AC: 23907 AN: 152078 Hom.: 2260 Cov.: 31 AF XY: 0.154 AC XY: 11428 AN XY: 74340

Gnomad4 AFR AF: 0.0674

Gnomad4 AMR AF: 0.141

Gnomad4 ASJ AF: 0.150

Gnomad4 EAS AF: 0.0676

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.210

Gnomad4 NFE AF: 0.219

Gnomad4 OTH AF: 0.148

Alfa AF: 0.202 Hom.: 7021

Bravo AF: 0.150

TwinsUK AF: 0.208 AC: 771

ALSPAC AF: 0.216 AC: 832

ESP6500AA AF: 0.0724 AC: 318

ESP6500EA AF: 0.213 AC: 1831

ExAC AF: 0.162 AC: 19637

Asia WGS AF: 0.0770 AC: 268 AN: 3478

EpiCase AF: 0.220

EpiControl AF: 0.220

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 1C Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 27, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Charcot-Marie-Tooth disease Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, London Health Sciences Centre	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

This variant is associated with the following publications: (PMID: 25342198, 24668782) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	0.082
Dann	Benign	0.17
DEOGEN2	Benign	0.25	T;T;.;T;.;T;T;T;T;.;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.010	N
MetaRNN	Benign	0.0026	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	N;N;N;N;N;N;N;N;.;.;N;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.39	T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;.;.;T;.;T
Polyphen		0.0	B;B;.;B;.;B;B;B;.;.;.;.;.
Vest4		0.063
MPC		0.12
ClinPred		0.00030	T
GERP RS		1.1
Varity_R		0.016
gMVP		0.38

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: rs4280262; hg19: chr16-11647492; COSMIC: COSV59654952; COSMIC: COSV59654952;