16-11548386-T-C

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.*1251A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.378 in 453,582 control chromosomes in the GnomAD database, including 32,870 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (10708 hom., cov: 31)
  • Exomes 𝑓: 0.38 (22162 hom.)
• Consequence: LITAF NM_001136472.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.40

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=-0.92).
• BP6: Variant 16-11548386-T-C is Benign according to our data. Variant chr16-11548386-T-C is described in ClinVar as [Benign]. Clinvar id is 317757.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LITAF	NM_001136472.2	c.*1251A>G		3_prime_UTR_variant	4/4	ENST00000622633.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LITAF	ENST00000622633.5	c.*1251A>G		3_prime_UTR_variant	4/4	1	NM_001136472.2	P1
LITAF	ENST00000339430.9	c.*1251A>G		3_prime_UTR_variant	4/4	1		P1
LITAF	ENST00000571688.5	c.*1251A>G		3_prime_UTR_variant	4/4	1		P1
LITAF	ENST00000413364.6	c.*1376A>G		3_prime_UTR_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56458 AN: 151692 Hom.: 10693 Cov.: 31

Gnomad AFR AF: 0.390

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.395

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.385

Gnomad NFE AF: 0.364

Gnomad OTH AF: 0.355

GnomAD3 exomes AF: 0.388 AC: 50577 AN: 130444 Hom.: 10109 AF XY: 0.391 AC XY: 27818 AN XY: 71208

Gnomad AFR exome AF: 0.399

Gnomad AMR exome AF: 0.358

Gnomad ASJ exome AF: 0.407

Gnomad EAS exome AF: 0.535

Gnomad SAS exome AF: 0.414

Gnomad FIN exome AF: 0.338

Gnomad NFE exome AF: 0.362

Gnomad OTH exome AF: 0.370

GnomAD4 exome AF: 0.381 AC: 114843 AN: 301770 Hom.: 22162 Cov.: 0 AF XY: 0.386 AC XY: 66371 AN XY: 171986

Gnomad4 AFR exome AF: 0.398

Gnomad4 AMR exome AF: 0.358

Gnomad4 ASJ exome AF: 0.409

Gnomad4 EAS exome AF: 0.533

Gnomad4 SAS exome AF: 0.418

Gnomad4 FIN exome AF: 0.339

Gnomad4 NFE exome AF: 0.363

Gnomad4 OTH exome AF: 0.373

GnomAD4 genome AF: 0.372 AC: 56518 AN: 151812 Hom.: 10708 Cov.: 31 AF XY: 0.373 AC XY: 27638 AN XY: 74166

Gnomad4 AFR AF: 0.390

Gnomad4 AMR AF: 0.331

Gnomad4 ASJ AF: 0.395

Gnomad4 EAS AF: 0.520

Gnomad4 SAS AF: 0.425

Gnomad4 FIN AF: 0.327

Gnomad4 NFE AF: 0.364

Gnomad4 OTH AF: 0.362

Alfa AF: 0.365 Hom.: 10776

Bravo AF: 0.375

Asia WGS AF: 0.496 AC: 1726 AN: 3478

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	-0.92
Cadd	Benign	0.44
Dann	Benign	0.43

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: rs7102; hg19: chr16-11642242;