16-11548841-A-G

Variant names:

• chr16-11548841-A-G
• rs1198
• NM_001136472.2:c.*796T>C

Variant summary

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

The NM_001136472.2(LITAF):​c.*796T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 453,402 control chromosomes in the GnomAD database, including 5,495 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 0.18 (2720 hom., cov: 31)
  • Exomes 𝑓: 0.13 (2775 hom.)
• Consequence: LITAF NM_001136472.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.919
• Publications: 16 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LITAF	NM_001136472.2	c.*796T>C		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.*796T>C		3_prime_UTR_variant	Exon 4 of 4	1	NM_001136472.2	ENSP00000483114.1
LITAF	ENST00000339430.9	c.*796T>C		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000340118.5
LITAF	ENST00000571688.6	c.*796T>C		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000459533.1
LITAF	ENST00000413364.6	c.*921T>C		3_prime_UTR_variant	Exon 5 of 5	2		ENSP00000397958.2

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27020 AN: 151818 Hom.: 2718 Cov.: 31

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.217

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.0925

Gnomad SAS AF: 0.0932

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.153

GnomAD2 exomes AF: 0.122 AC: 15950 AN: 130224 AF XY: 0.120

Gnomad AFR exome AF: 0.288

Gnomad AMR exome AF: 0.0753

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.0910

Gnomad FIN exome AF: 0.159

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.128 AC: 38634 AN: 301466 Hom.: 2775 Cov.: 0 AF XY: 0.123 AC XY: 21219 AN XY: 171822

African (AFR) AF: 0.289 AC: 2452 AN: 8488

American (AMR) AF: 0.0759 AC: 2066 AN: 27226

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 1185 AN: 10776

East Asian (EAS) AF: 0.0886 AC: 816 AN: 9210

South Asian (SAS) AF: 0.0970 AC: 5776 AN: 59526

European-Finnish (FIN) AF: 0.157 AC: 1942 AN: 12364

Middle Eastern (MID) AF: 0.134 AC: 154 AN: 1150

European-Non Finnish (NFE) AF: 0.141 AC: 22301 AN: 158698

Other (OTH) AF: 0.138 AC: 1942 AN: 14028

GnomAD4 genome AF: 0.178 AC: 27040 AN: 151936 Hom.: 2720 Cov.: 31 AF XY: 0.176 AC XY: 13075 AN XY: 74270

African (AFR) AF: 0.287 AC: 11875 AN: 41402

American (AMR) AF: 0.117 AC: 1788 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 349 AN: 3470

East Asian (EAS) AF: 0.0931 AC: 481 AN: 5164

South Asian (SAS) AF: 0.0924 AC: 445 AN: 4816

European-Finnish (FIN) AF: 0.170 AC: 1794 AN: 10552

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9746 AN: 67968

Other (OTH) AF: 0.153 AC: 323 AN: 2106

Alfa AF: 0.177 Hom.: 1690

Bravo AF: 0.179

Asia WGS AF: 0.139 AC: 482 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 13, 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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.0
DANN	Benign	0.47
PhyloP100		0.92
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: rs1198; hg19: chr16-11642697;