16-11548222-G-T

Variant names:

• chr16-11548222-G-T
• rs80119580
• NM_001136472.2:c.*1415C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001136472.2(LITAF):​c.*1415C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 454,018 control chromosomes in the GnomAD database, including 344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.034 (275 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (69 hom.)
• Consequence: LITAF NM_001136472.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0920
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-11548222-G-T is Benign according to our data. Variant chr16-11548222-G-T is described in ClinVar as [Benign]. Clinvar id is 317756.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LITAF	NM_001136472.2	c.*1415C>A		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.*1415C>A		3_prime_UTR_variant	Exon 4 of 4	1	NM_001136472.2	ENSP00000483114.1
LITAF	ENST00000339430.9	c.*1415C>A		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000340118.5
LITAF	ENST00000571688.6	c.*1415C>A		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000459533.1
LITAF	ENST00000413364.6	c.*1540C>A		3_prime_UTR_variant	Exon 5 of 5	2		ENSP00000397958.2

Frequencies

GnomAD3 genomes AF: 0.0336 AC: 5113 AN: 152110 Hom.: 272 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.0249

GnomAD2 exomes AF: 0.00775 AC: 1011 AN: 130422 AF XY: 0.00610

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.00620

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000483

Gnomad OTH exome AF: 0.00500

GnomAD4 exome AF: 0.00473 AC: 1426 AN: 301790 Hom.: 69 Cov.: 0 AF XY: 0.00349 AC XY: 600 AN XY: 171994

African (AFR) AF: 0.120 AC: 1029 AN: 8552

American (AMR) AF: 0.00634 AC: 173 AN: 27274

Ashkenazi Jewish (ASJ) AF: 0.00408 AC: 44 AN: 10786

East Asian (EAS) AF: 0.00 AC: 0 AN: 9210

South Asian (SAS) AF: 0.000285 AC: 17 AN: 59650

European-Finnish (FIN) AF: 0.000162 AC: 2 AN: 12364

Middle Eastern (MID) AF: 0.000870 AC: 1 AN: 1150

European-Non Finnish (NFE) AF: 0.000283 AC: 45 AN: 158764

Other (OTH) AF: 0.00819 AC: 115 AN: 14040

GnomAD4 genome AF: 0.0337 AC: 5128 AN: 152228 Hom.: 275 Cov.: 32 AF XY: 0.0327 AC XY: 2436 AN XY: 74432

African (AFR) AF: 0.117 AC: 4837 AN: 41508

American (AMR) AF: 0.0131 AC: 200 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000367 AC: 25 AN: 68030

Other (OTH) AF: 0.0246 AC: 52 AN: 2112

Alfa AF: 0.0136 Hom.: 35

Bravo AF: 0.0387

Asia WGS AF: 0.00808 AC: 28 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

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.0
DANN	Benign	0.51
PhyloP100		0.092
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: rs80119580; hg19: chr16-11642078;