rs201283647

chr16-11553608-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM1 BP4_Moderate BP6 BS1 BS2

The NM_001136472.2(LITAF):c.302A>G(p.Lys101Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000375 in 1,614,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: LITAF NM_001136472.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 4.17

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 -9 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=0.08748722).
• BP6: Variant 16-11553608-T-C is Benign according to our data. Variant chr16-11553608-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 404114.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000197 (30/152266) while in subpopulation NFE AF= 0.000353 (24/68012). AF 95% confidence interval is 0.000243. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LITAF	NM_001136472.2	c.302A>G	p.Lys101Arg	missense_variant	3/4	ENST00000622633.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LITAF	ENST00000622633.5	c.302A>G	p.Lys101Arg	missense_variant	3/4	1	NM_001136472.2	P1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000247 AC: 62 AN: 251232 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135782

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000476

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000394 AC: 576 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.000399 AC XY: 290 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000496

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74454

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000317 Hom.: 0

Bravo AF: 0.000249

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000491

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2020	This variant is associated with the following publications: (PMID: 25245565, 26392352, 32376792) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 15, 2019	- -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 101 of the LITAF protein (p.Lys101Arg). This variant is present in population databases (rs201283647, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with peripheral neuropathy (PMID: 26392352, 32376792). ClinVar contains an entry for this variant (Variation ID: 404114). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 15, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.15
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T;.;T;.;T;.;T;T;T;.;.;.;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.087	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.7	L;L;L;L;L;L;.;L;L;.;.;L;.;.
MutationTaster	Benign	1.0	D;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.54	T
Sift4G	Benign	0.35	T;T;T;T;T;T;T;T;T;.;.;T;.;T
Polyphen		0.92	P;P;.;P;.;P;.;P;P;.;.;.;.;.
Vest4		0.35
MVP		0.98
MPC		0.43
ClinPred		0.049	T
GERP RS		4.3
Varity_R		0.059
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.60		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.60		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201283647; hg19: chr16-11647464;