16-11553565-GG-AT

Variant names:

• chr16-11553565-GG-AT
• NM_001136472.2:c.344_345delCCinsAT
• LITAF p.Thr115Asn

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS1_Very_Strong PM1

The NM_001136472.2(LITAF):​c.344_345delCCinsAT​(p.Thr115Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T115I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LITAF NM_001136472.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.18
• 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: Pathogenic. The variant received 10 ACMG points.

• PS1: Transcript NM_001136472.2 (LITAF) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001136472.2

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136472.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LITAF	NM_001136472.2	MANE Select	c.344_345delCCinsAT	p.Thr115Asn	missense	N/A	NP_001129944.1	Q99732-1
	LITAF	NM_004862.4		c.344_345delCCinsAT	p.Thr115Asn	missense	N/A	NP_004853.2	Q99732-1
	LITAF	NM_001136473.1		c.344_345delCCinsAT	p.Thr115Asn	missense	N/A	NP_001129945.1	Q99732-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LITAF	ENST00000622633.5	TSL:1 MANE Select	c.344_345delCCinsAT	p.Thr115Asn	missense	N/A	ENSP00000483114.1	Q99732-1
	LITAF	ENST00000339430.9	TSL:1	c.344_345delCCinsAT	p.Thr115Asn	missense	N/A	ENSP00000340118.5	Q99732-1
	LITAF	ENST00000570904.5	TSL:1	c.344_345delCCinsAT	p.Thr115Asn	missense	N/A	ENSP00000459138.1	Q99732-1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.2

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr16-11647421;