7-44513605-C-G

Variant names:

• chr7-44513605-C-G
• rs217435
• NM_001101648.2:c.3841G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001101648.2(NPC1L1):​c.3841G>C​(p.Glu1281Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPC1L1 NM_001101648.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0660

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0800558).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1L1	NM_001101648.2	c.3841G>C	p.Glu1281Gln	missense_variant	Exon 19 of 19	ENST00000381160.8	NP_001095118.1
NPC1L1	NM_013389.3	c.3922G>C	p.Glu1308Gln	missense_variant	Exon 20 of 20		NP_037521.2
NPC1L1	XM_011515326.4	c.3646G>C	p.Glu1216Gln	missense_variant	Exon 18 of 18		XP_011513628.1
NPC1L1	XM_011515328.3	c.2200G>C	p.Glu734Gln	missense_variant	Exon 16 of 16		XP_011513630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1L1	ENST00000381160.8	c.3841G>C	p.Glu1281Gln	missense_variant	Exon 19 of 19	1	NM_001101648.2	ENSP00000370552.3
NPC1L1	ENST00000289547.8	c.3922G>C	p.Glu1308Gln	missense_variant	Exon 20 of 20	1		ENSP00000289547.4
NPC1L1	ENST00000546276.5	c.3703G>C	p.Glu1235Gln	missense_variant	Exon 18 of 18	1		ENSP00000438033.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.4
DANN	Benign	0.73
DEOGEN2	Benign	0.093	T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.60	T;T;T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.080	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.19	N;N;N
REVEL	Benign	0.037
Sift	Benign	0.53	T;T;T
Sift4G	Benign	0.19	T;T;T
Vest4		0.054
MutPred		0.33		Loss of helix (P = 0.0041);.;.;
MVP		0.61
MPC		0.15
ClinPred		0.050	T
GERP RS		-0.69
Varity_R		0.054
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs217435; hg19: chr7-44553204;