7-44540232-CAC-TAG

Variant names:

• chr7-44540232-CAC-TAG
• NM_001101648.2:c.163_165delGTGinsCTA
• NPC1L1 p.Val55Leu

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001101648.2(NPC1L1):​c.163_165delGTGinsCTA​(p.Val55Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPC1L1 NM_001101648.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.05
• Publications: 0 publications found

Genes affected

NPC1L1 (HGNC:7898): (NPC1 like intracellular cholesterol transporter 1) The protein encoded by this gene is a multi-pass membrane protein. It contains a conserved N-terminal Niemann-Pick C1 (NPC1) domain and a putative sterol-sensing domain (SSD) which includes a YQRL motif functioning as a plasma membrane to trans-Golgi network transport signal in other proteins. This protein takes up free cholesterol into cells through vesicular endocytosis and plays a critical role in the absorption of intestinal cholesterol. It also has the ability to transport alpha-tocopherol (vitamin E). The drug ezetimibe targets this protein and inhibits the absorption of intestinal cholesterol and alpha-tocopherol. In addition, this protein may play a critical role in regulating lipid metabolism. Polymorphic variations in this gene are associated with plasma total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels and coronary heart disease (CHD) risk. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001101648.2. 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
	NPC1L1	NM_001101648.2	MANE Select	c.163_165delGTGinsCTA	p.Val55Leu	missense	N/A	NP_001095118.1	A0A0C4DFX6
	NPC1L1	NM_013389.3		c.163_165delGTGinsCTA	p.Val55Leu	missense	N/A	NP_037521.2	Q9UHC9-1
	NPC1L1	NM_001300967.2		c.163_165delGTGinsCTA	p.Val55Leu	missense	N/A	NP_001287896.1	Q9UHC9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1L1	ENST00000381160.8	TSL:1 MANE Select	c.163_165delGTGinsCTA	p.Val55Leu	missense	N/A	ENSP00000370552.3	A0A0C4DFX6
	NPC1L1	ENST00000289547.8	TSL:1	c.163_165delGTGinsCTA	p.Val55Leu	missense	N/A	ENSP00000289547.4	Q9UHC9-1
	NPC1L1	ENST00000546276.5	TSL:1	c.163_165delGTGinsCTA	p.Val55Leu	missense	N/A	ENSP00000438033.1	A0A0C4DGG6

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		8.1

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: chr7-44579831;