16-11548820-T-TA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001136472.2(LITAF):c.*816_*817insT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000212 in 451,982 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: LITAF NM_001136472.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000264 (40/151230) while in subpopulation NFE AF= 0.000413 (28/67800). AF 95% confidence interval is 0.000293. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LITAF	NM_001136472.2	c.*816_*817insT		3_prime_UTR_variant	4/4	ENST00000622633.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LITAF	ENST00000622633.5	c.*816_*817insT		3_prime_UTR_variant	4/4	1	NM_001136472.2	P1
LITAF	ENST00000339430.9	c.*816_*817insT		3_prime_UTR_variant	4/4	1		P1
LITAF	ENST00000571688.5	c.*816_*817insT		3_prime_UTR_variant	4/4	1		P1
LITAF	ENST00000413364.6	c.*941_*942insT		3_prime_UTR_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.000264 AC: 40 AN: 151230 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

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: 0.000413

Gnomad OTH AF: 0.000482

GnomAD3 exomes AF: 0.000201 AC: 26 AN: 129082 Hom.: 0 AF XY: 0.000255 AC XY: 18 AN XY: 70478

Gnomad AFR exome AF: 0.000165

Gnomad AMR exome AF: 0.0000416

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000228

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000385

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000186 AC: 56 AN: 300752 Hom.: 0 Cov.: 0 AF XY: 0.000216 AC XY: 37 AN XY: 171462

Gnomad4 AFR exome AF: 0.000476

Gnomad4 AMR exome AF: 0.0000369

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000135

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000265

Gnomad4 OTH exome AF: 0.0000715

GnomAD4 genome AF: 0.000264 AC: 40 AN: 151230 Hom.: 0 Cov.: 31 AF XY: 0.000230 AC XY: 17 AN XY: 73830

Gnomad4 AFR AF: 0.000218

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000413

Gnomad4 OTH AF: 0.000482

Alfa AF: 0.000336 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease, type I Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs758850868; hg19: chr16-11642676;