chr16-11553636-T-C

Variant names:

• chr16-11553636-T-C
• rs4280262
• NM_001136472.2:c.274A>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.274A>G​(p.Ile92Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 1,613,820 control chromosomes in the GnomAD database, including 33,324 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2260 hom., cov: 31)
  • Exomes 𝑓: 0.20 (31064 hom.)
• Consequence: LITAF NM_001136472.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: 0.370
• Publications: 50 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 (MetaRNN=0.0026205182).
• BP6: Variant 16-11553636-T-C is Benign according to our data. Variant chr16-11553636-T-C is described in ClinVar as Benign. ClinVar VariationId is 317782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

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.274A>G	p.Ile92Val	missense	Exon 3 of 4	NP_001129944.1	Q99732-1
	LITAF	NM_004862.4		c.274A>G	p.Ile92Val	missense	Exon 3 of 4	NP_004853.2	Q99732-1
	LITAF	NM_001136473.1		c.274A>G	p.Ile92Val	missense	Exon 3 of 5	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.274A>G	p.Ile92Val	missense	Exon 3 of 4	ENSP00000483114.1	Q99732-1
	LITAF	ENST00000339430.9	TSL:1	c.274A>G	p.Ile92Val	missense	Exon 3 of 4	ENSP00000340118.5	Q99732-1
	LITAF	ENST00000570904.5	TSL:1	c.274A>G	p.Ile92Val	missense	Exon 3 of 4	ENSP00000459138.1	Q99732-1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23901 AN: 151960 Hom.: 2259 Cov.: 31

Gnomad AFR AF: 0.0674

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.0675

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.150

GnomAD2 exomes AF: 0.166 AC: 41592 AN: 250932 AF XY: 0.167

Gnomad AFR exome AF: 0.0624

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.0648

Gnomad FIN exome AF: 0.213

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.179

GnomAD4 exome AF: 0.200 AC: 292273 AN: 1461742 Hom.: 31064 Cov.: 34 AF XY: 0.198 AC XY: 143685 AN XY: 727160

African (AFR) AF: 0.0587 AC: 1966 AN: 33480

American (AMR) AF: 0.137 AC: 6123 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 4158 AN: 26136

East Asian (EAS) AF: 0.0673 AC: 2673 AN: 39696

South Asian (SAS) AF: 0.104 AC: 9008 AN: 86252

European-Finnish (FIN) AF: 0.209 AC: 11163 AN: 53396

Middle Eastern (MID) AF: 0.124 AC: 715 AN: 5768

European-Non Finnish (NFE) AF: 0.221 AC: 245844 AN: 1111908

Other (OTH) AF: 0.176 AC: 10623 AN: 60390

GnomAD4 genome AF: 0.157 AC: 23907 AN: 152078 Hom.: 2260 Cov.: 31 AF XY: 0.154 AC XY: 11428 AN XY: 74340

African (AFR) AF: 0.0674 AC: 2795 AN: 41496

American (AMR) AF: 0.141 AC: 2155 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 520 AN: 3468

East Asian (EAS) AF: 0.0676 AC: 350 AN: 5174

South Asian (SAS) AF: 0.101 AC: 487 AN: 4818

European-Finnish (FIN) AF: 0.210 AC: 2213 AN: 10560

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.219 AC: 14868 AN: 67966

Other (OTH) AF: 0.148 AC: 312 AN: 2104

Alfa AF: 0.192 Hom.: 9175

Bravo AF: 0.150

TwinsUK AF: 0.208 AC: 771

ALSPAC AF: 0.216 AC: 832

ESP6500AA AF: 0.0724 AC: 318

ESP6500EA AF: 0.213 AC: 1831

ExAC AF: 0.162 AC: 19637

Asia WGS AF: 0.0770 AC: 268 AN: 3478

EpiCase AF: 0.220

EpiControl AF: 0.220

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Charcot-Marie-Tooth disease type 1C (5)
-	1	1	Charcot-Marie-Tooth disease (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.082
DANN	Benign	0.17
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	N
PhyloP100		0.37
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.55	N
REVEL	Benign	0.20
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.063
MPC		0.12
ClinPred		0.00030	T
GERP RS		1.1
Varity_R		0.016
gMVP		0.38
Mutation Taster		=299/1	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: rs4280262; hg19: chr16-11647492; COSMIC: COSV59654952; COSMIC: COSV59654952;