rs34448402

Positions:

• chr16-11553577-G-A
• chr16-11553577-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001136472.2(LITAF):​c.333C>T​(p.Ala111Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00311 in 1,614,134 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (9 hom.)
• Consequence: LITAF NM_001136472.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.44

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 16-11553577-G-A is Benign according to our data. Variant chr16-11553577-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 221057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-11553577-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.44 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00252 (383/152276) while in subpopulation AMR AF= 0.00366 (56/15292). AF 95% confidence interval is 0.00326. There are 1 homozygotes in gnomad4. There are 166 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 383 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LITAF	NM_001136472.2	c.333C>T	p.Ala111Ala	synonymous_variant	3/4	ENST00000622633.5	NP_001129944.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LITAF	ENST00000622633.5	c.333C>T	p.Ala111Ala	synonymous_variant	3/4	1	NM_001136472.2	ENSP00000483114.1

Frequencies

GnomAD3 genomes AF: 0.00251 AC: 382 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00362

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00213 AC: 536 AN: 251186 Hom.: 0 AF XY: 0.00227 AC XY: 308 AN XY: 135764

Gnomad AFR exome AF: 0.000924

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.000463

Gnomad NFE exome AF: 0.00352

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00317 AC: 4641 AN: 1461858 Hom.: 9 Cov.: 31 AF XY: 0.00311 AC XY: 2262 AN XY: 727226

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.00264

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.000524

Gnomad4 NFE exome AF: 0.00378

Gnomad4 OTH exome AF: 0.00296

GnomAD4 genome AF: 0.00252 AC: 383 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.00223 AC XY: 166 AN XY: 74458

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00363

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00323 Hom.: 0

Bravo AF: 0.00277

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00420

EpiControl AF: 0.00468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 30, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Charcot-Marie-Tooth disease type 1C Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	LITAF: BP4, BP7 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2019

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
BayesDel_noAF	Benign	-0.64
CADD	Benign	1.9
DANN	Benign	0.45

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

Other links and lift over

dbSNP: rs34448402; hg19: chr16-11647433;