rs752978718

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4BS1_SupportingBS2

The NM_001136472.2(LITAF):c.151C>T(p.Pro51Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

LITAF
NM_001136472.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.92

Variant links:

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]

LITAF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. 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

BP4

Computational evidence support a benign effect (MetaRNN=0.31176534).

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000212 (31/1461892) while in subpopulation AMR AF= 0.000514 (23/44724). AF 95% confidence interval is 0.000351. There are 0 homozygotes in gnomad4_exome. There are 15 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 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LITAF	NM_001136472.2 linkuse as main transcript	c.151C>T	p.Pro51Ser	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 linkuse as main transcript	c.151C>T	p.Pro51Ser	missense_variant	2/4	1	NM_001136472.2	ENSP00000483114	P1	Q99732-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

251274

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000514

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:

0.00000629

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 1C

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 13, 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 404113). This variant has not been reported in the literature in individuals affected with LITAF-related conditions. This variant is present in population databases (rs752978718, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 51 of the LITAF protein (p.Pro51Ser). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;T;.;T;.;T;T;T;T;T;.;.;.;.;T;T

Eigen

Benign

0.12

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.89

.;D;.;.;D;.;D;.;.;D;D;D;D;D;D;D

M_CAP

Benign

0.074

MetaRNN

Benign

0.31

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.18

MutationAssessor

Benign

1.8

L;L;L;L;L;L;.;L;L;.;.;L;.;.;.;.

MutationTaster

Benign

1.0

D;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.9

.;.;N;N;N;.;.;.;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.40

Sift

Benign

0.033

.;.;D;D;D;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.59

T;T;T;T;T;T;T;T;T;.;.;T;.;T;T;T

Polyphen

0.48

P;P;.;P;D;P;.;P;P;.;.;.;.;.;.;.

Vest4

0.36

MutPred

0.24

Gain of glycosylation at P51 (P = 0.0254);Gain of glycosylation at P51 (P = 0.0254);Gain of glycosylation at P51 (P = 0.0254);Gain of glycosylation at P51 (P = 0.0254);Gain of glycosylation at P51 (P = 0.0254);Gain of glycosylation at P51 (P = 0.0254);Gain of glycosylation at P51 (P = 0.0254);Gain of glycosylation at P51 (P = 0.0254);Gain of glycosylation at P51 (P = 0.0254);Gain of glycosylation at P51 (P = 0.0254);Gain of glycosylation at P51 (P = 0.0254);Gain of glycosylation at P51 (P = 0.0254);Gain of glycosylation at P51 (P = 0.0254);Gain of glycosylation at P51 (P = 0.0254);Gain of glycosylation at P51 (P = 0.0254);.;

MVP

1.0

MPC

0.23

ClinPred

0.30

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.038

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over