16-11548821-A-T

Position:

• chr16-11548821-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. Variant has been reported in ClinVar as Benign (★).

• 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

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 16-11548821-A-T is Benign according to our data. Variant chr16-11548821-A-T is described in ClinVar as [Benign]. Clinvar id is 317764.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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/exons	MANE	UniProt
LITAF	NM_001136472.2	c.*816T>A		3_prime_UTR_variant	4/4	ENST00000622633.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LITAF	ENST00000622633.5	c.*816T>A		3_prime_UTR_variant	4/4	1	NM_001136472.2	P1
LITAF	ENST00000339430.9	c.*816T>A		3_prime_UTR_variant	4/4	1		P1
LITAF	ENST00000571688.5	c.*816T>A		3_prime_UTR_variant	4/4	1		P1
LITAF	ENST00000413364.6	c.*941T>A		3_prime_UTR_variant	5/5	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

GnomAD3 exomes AF: 0.00816 AC: 1042 AN: 127772 Hom.: 34 AF XY: 0.00708 AC XY: 495 AN XY: 69882

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 SAS exome AF: 0.00238

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

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.00609

Gnomad4 ASJ exome AF: 0.000187

Gnomad4 EAS exome AF: 0.000652

Gnomad4 SAS exome AF: 0.00218

Gnomad4 FIN exome AF: 0.00527

Gnomad4 NFE exome AF: 0.00206

Gnomad4 OTH exome AF: 0.0109

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

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.0117

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.00272

Gnomad4 FIN AF: 0.00423

Gnomad4 NFE AF: 0.00190

Gnomad4 OTH AF: 0.0215

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

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.25
DANN	Benign	0.15

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