16-11548841-A-G

Position:

• chr16-11548841-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_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. Variant has been reported in ClinVar as Benign (★★).

• 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

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 16-11548841-A-G is Benign according to our data. Variant chr16-11548841-A-G is described in ClinVar as [Benign]. Clinvar id is 317765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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/exons	MANE	Protein	UniProt
LITAF	NM_001136472.2	c.*796T>C		3_prime_UTR_variant	4/4	ENST00000622633.5	NP_001129944.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LITAF	ENST00000622633.5	c.*796T>C		3_prime_UTR_variant	4/4	1	NM_001136472.2	ENSP00000483114	P1
LITAF	ENST00000339430.9	c.*796T>C		3_prime_UTR_variant	4/4	1		ENSP00000340118	P1
LITAF	ENST00000571688.5	c.*796T>C		3_prime_UTR_variant	4/4	1		ENSP00000459533	P1
LITAF	ENST00000413364.6	c.*921T>C		3_prime_UTR_variant	5/5	2		ENSP00000397958

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

GnomAD3 exomes AF: 0.122 AC: 15950 AN: 130224 Hom.: 1172 AF XY: 0.120 AC XY: 8547 AN XY: 71084

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 SAS exome AF: 0.0939

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

Gnomad4 AFR exome AF: 0.289

Gnomad4 AMR exome AF: 0.0759

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.0886

Gnomad4 SAS exome AF: 0.0970

Gnomad4 FIN exome AF: 0.157

Gnomad4 NFE exome AF: 0.141

Gnomad4 OTH exome AF: 0.138

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

Gnomad4 AFR AF: 0.287

Gnomad4 AMR AF: 0.117

Gnomad4 ASJ AF: 0.101

Gnomad4 EAS AF: 0.0931

Gnomad4 SAS AF: 0.0924

Gnomad4 FIN AF: 0.170

Gnomad4 NFE AF: 0.143

Gnomad4 OTH AF: 0.153

Alfa AF: 0.154 Hom.: 643

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.0
DANN	Benign	0.47

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: rs1198; hg19: chr16-11642697;