16-11549720-G-C

Variant names:

• chr16-11549720-G-C
• rs281865135
• NM_001136472.2:c.403C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_001136472.2(LITAF):​c.403C>G​(p.Pro135Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P135S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LITAF NM_001136472.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.61
• 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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-11549720-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 41230.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 16-11549720-G-C is Pathogenic according to our data. Variant chr16-11549720-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2502274.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LITAF	NM_001136472.2	c.403C>G	p.Pro135Ala	missense_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.403C>G	p.Pro135Ala	missense_variant	Exon 4 of 4	1	NM_001136472.2	ENSP00000483114.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Dec 22, 2022

Gemeinschaftspraxis fuer Humangenetik Dresden

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This mutation c.403C>G, p.(Pro135Ala) is not reported in HGMD 2022.4, gnomAD (v2.1.1) or LOVD. But on same aminoacid position the pathogenic mutations p.(Pro135Ser), p.(Pro135Thr) and p.(Pro135Arg) for phenotype Charcot-Marie-Tooth disease Typ 1C are known. In summary, the p.Arg270Pro variant meets our criteria to be classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;D;D;.;D;D;D;.
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	.;D;.;.;D;.;.;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M;M;M;M;.;M;M;.;.
PhyloP100		7.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-7.7	.;.;D;.;.;.;.;.;.
REVEL	Pathogenic	0.84
Sift	Benign	0.045	.;.;D;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;.;.
Polyphen		1.0	D;D;D;D;.;D;D;.;.
Vest4		0.78
MutPred		0.82		Gain of catalytic residue at P135 (P = 0.0248);Gain of catalytic residue at P135 (P = 0.0248);Gain of catalytic residue at P135 (P = 0.0248);Gain of catalytic residue at P135 (P = 0.0248);.;Gain of catalytic residue at P135 (P = 0.0248);Gain of catalytic residue at P135 (P = 0.0248);Gain of catalytic residue at P135 (P = 0.0248);Gain of catalytic residue at P135 (P = 0.0248);
MVP		1.0
MPC		0.64
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.68
gMVP		0.77

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: rs281865135; hg19: chr16-11643576;