16-11548386-T-C

Variant names:

• chr16-11548386-T-C
• rs7102
• NM_001136472.2:c.*1251A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001136472.2(LITAF):​c.*1251A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.378 in 453,582 control chromosomes in the GnomAD database, including 32,870 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10708 hom., cov: 31)
  • Exomes 𝑓: 0.38 (22162 hom.)
• Consequence: LITAF NM_001136472.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.40
• Publications: 24 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 16-11548386-T-C is Benign according to our data. Variant chr16-11548386-T-C is described in ClinVar as [Benign]. Clinvar id is 317757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LITAF	NM_001136472.2	c.*1251A>G		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.*1251A>G		3_prime_UTR_variant	Exon 4 of 4	1	NM_001136472.2	ENSP00000483114.1
LITAF	ENST00000339430.9	c.*1251A>G		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000340118.5
LITAF	ENST00000571688.6	c.*1251A>G		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000459533.1
LITAF	ENST00000413364.6	c.*1376A>G		3_prime_UTR_variant	Exon 5 of 5	2		ENSP00000397958.2

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56458 AN: 151692 Hom.: 10693 Cov.: 31

Gnomad AFR AF: 0.390

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.395

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.385

Gnomad NFE AF: 0.364

Gnomad OTH AF: 0.355

GnomAD2 exomes AF: 0.388 AC: 50577 AN: 130444 AF XY: 0.391

Gnomad AFR exome AF: 0.399

Gnomad AMR exome AF: 0.358

Gnomad ASJ exome AF: 0.407

Gnomad EAS exome AF: 0.535

Gnomad FIN exome AF: 0.338

Gnomad NFE exome AF: 0.362

Gnomad OTH exome AF: 0.370

GnomAD4 exome AF: 0.381 AC: 114843 AN: 301770 Hom.: 22162 Cov.: 0 AF XY: 0.386 AC XY: 66371 AN XY: 171986

African (AFR) AF: 0.398 AC: 3406 AN: 8554

American (AMR) AF: 0.358 AC: 9768 AN: 27272

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 4408 AN: 10786

East Asian (EAS) AF: 0.533 AC: 4912 AN: 9210

South Asian (SAS) AF: 0.418 AC: 24911 AN: 59646

European-Finnish (FIN) AF: 0.339 AC: 4189 AN: 12364

Middle Eastern (MID) AF: 0.374 AC: 430 AN: 1150

European-Non Finnish (NFE) AF: 0.363 AC: 57581 AN: 158750

Other (OTH) AF: 0.373 AC: 5238 AN: 14038

GnomAD4 genome AF: 0.372 AC: 56518 AN: 151812 Hom.: 10708 Cov.: 31 AF XY: 0.373 AC XY: 27638 AN XY: 74166

African (AFR) AF: 0.390 AC: 16135 AN: 41380

American (AMR) AF: 0.331 AC: 5046 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 1371 AN: 3468

East Asian (EAS) AF: 0.520 AC: 2680 AN: 5156

South Asian (SAS) AF: 0.425 AC: 2040 AN: 4804

European-Finnish (FIN) AF: 0.327 AC: 3437 AN: 10524

Middle Eastern (MID) AF: 0.380 AC: 111 AN: 292

European-Non Finnish (NFE) AF: 0.364 AC: 24706 AN: 67930

Other (OTH) AF: 0.362 AC: 765 AN: 2112

Alfa AF: 0.365 Hom.: 13678

Bravo AF: 0.375

Asia WGS AF: 0.496 AC: 1726 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 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. -

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	-0.92
CADD	Benign	0.44
DANN	Benign	0.43
PhyloP100		-1.4
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: rs7102; hg19: chr16-11642242;