16-11548821-A-T

Variant names:

• chr16-11548821-A-T
• rs7187810
• NM_001136472.2:c.*816T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001136472.2(LITAF):​c.*816T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 450,504 control chromosomes in the GnomAD database, including 302 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.032 (246 hom., cov: 31)
  • Exomes 𝑓: 0.0058 (56 hom.)
• Consequence: LITAF NM_001136472.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.13
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease type 1C

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• Charcot-Marie-Tooth disease

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LITAF	NM_001136472.2	c.*816T>A		3_prime_UTR_variant	Exon 4 of 4	ENST00000622633.5	NP_001129944.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LITAF	ENST00000622633.5	c.*816T>A		3_prime_UTR_variant	Exon 4 of 4	1	NM_001136472.2	ENSP00000483114.1
LITAF	ENST00000339430.9	c.*816T>A		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000340118.5
LITAF	ENST00000571688.6	c.*816T>A		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000459533.1
LITAF	ENST00000413364.6	c.*941T>A		3_prime_UTR_variant	Exon 5 of 5	2		ENSP00000397958.2

Frequencies

GnomAD3 genomes AF: 0.0319 AC: 4820 AN: 151206 Hom.: 246 Cov.: 31

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.00271

Gnomad FIN AF: 0.00423

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.0213

GnomAD2 exomes AF: 0.00816 AC: 1042 AN: 127772 AF XY: 0.00708

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.00588

Gnomad ASJ exome AF: 0.000629

Gnomad EAS exome AF: 0.000590

Gnomad FIN exome AF: 0.00656

Gnomad NFE exome AF: 0.00282

Gnomad OTH exome AF: 0.00586

GnomAD4 exome AF: 0.00579 AC: 1733 AN: 299184 Hom.: 56 Cov.: 0 AF XY: 0.00494 AC XY: 843 AN XY: 170820

African (AFR) AF: 0.107 AC: 881 AN: 8236

American (AMR) AF: 0.00609 AC: 161 AN: 26448

Ashkenazi Jewish (ASJ) AF: 0.000187 AC: 2 AN: 10674

East Asian (EAS) AF: 0.000652 AC: 6 AN: 9204

South Asian (SAS) AF: 0.00218 AC: 129 AN: 59156

European-Finnish (FIN) AF: 0.00527 AC: 65 AN: 12332

Middle Eastern (MID) AF: 0.0106 AC: 12 AN: 1136

European-Non Finnish (NFE) AF: 0.00206 AC: 326 AN: 158104

Other (OTH) AF: 0.0109 AC: 151 AN: 13894

GnomAD4 genome AF: 0.0319 AC: 4824 AN: 151320 Hom.: 246 Cov.: 31 AF XY: 0.0317 AC XY: 2343 AN XY: 73978

African (AFR) AF: 0.107 AC: 4403 AN: 41230

American (AMR) AF: 0.0117 AC: 178 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5156

South Asian (SAS) AF: 0.00272 AC: 13 AN: 4784

European-Finnish (FIN) AF: 0.00423 AC: 44 AN: 10408

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00190 AC: 129 AN: 67766

Other (OTH) AF: 0.0215 AC: 45 AN: 2090

Alfa AF: 0.0150 Hom.: 21

Bravo AF: 0.0364

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.25
DANN	Benign	0.15
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7187810; hg19: chr16-11642677; COSMIC: COSV59655574; COSMIC: COSV59655574;