16-11548820-T-TA

Variant names:

• chr16-11548820-T-TA
• rs758850868
• NM_001136472.2:c.*816dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001136472.2(LITAF):​c.*816dupT 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• 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 -8 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 40 AD gene.

Transcripts

RefSeq

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

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

GnomAD2 exomes AF: 0.000201 AC: 26 AN: 129082 AF XY: 0.000255

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 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

African (AFR) AF: 0.000476 AC: 4 AN: 8404

American (AMR) AF: 0.0000369 AC: 1 AN: 27066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10752

East Asian (EAS) AF: 0.00 AC: 0 AN: 9208

South Asian (SAS) AF: 0.000135 AC: 8 AN: 59290

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1146

European-Non Finnish (NFE) AF: 0.000265 AC: 42 AN: 158552

Other (OTH) AF: 0.0000715 AC: 1 AN: 13982

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

African (AFR) AF: 0.000218 AC: 9 AN: 41210

American (AMR) AF: 0.000132 AC: 2 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000413 AC: 28 AN: 67800

Other (OTH) AF: 0.000482 AC: 1 AN: 2076

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.1

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: rs758850868; hg19: chr16-11642676;