NM_001101648.2:c.3573C>G

Variant names:

• chr7-44516144-G-C
• NM_001101648.2:c.3573C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001101648.2(NPC1L1):​c.3573C>G​(p.Ile1191Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,442 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NPC1L1 NM_001101648.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31736216).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1L1	NM_001101648.2	c.3573C>G	p.Ile1191Met	missense_variant	Exon 17 of 19	ENST00000381160.8	NP_001095118.1
NPC1L1	NM_013389.3	c.3654C>G	p.Ile1218Met	missense_variant	Exon 18 of 20		NP_037521.2
NPC1L1	XM_011515326.4	c.3378C>G	p.Ile1126Met	missense_variant	Exon 16 of 18		XP_011513628.1
NPC1L1	XM_011515328.3	c.1932C>G	p.Ile644Met	missense_variant	Exon 14 of 16		XP_011513630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1L1	ENST00000381160.8	c.3573C>G	p.Ile1191Met	missense_variant	Exon 17 of 19	1	NM_001101648.2	ENSP00000370552.3
NPC1L1	ENST00000289547.8	c.3654C>G	p.Ile1218Met	missense_variant	Exon 18 of 20	1		ENSP00000289547.4
NPC1L1	ENST00000546276.5	c.3435C>G	p.Ile1145Met	missense_variant	Exon 16 of 18	1		ENSP00000438033.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460442 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726368

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3654C>G (p.I1218M) alteration is located in exon 18 (coding exon 18) of the NPC1L1 gene. This alteration results from a C to G substitution at nucleotide position 3654, causing the isoleucine (I) at amino acid position 1218 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.20	T;T;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Uncertain	-0.095	T
MutationAssessor	Benign	0.97	L;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.20
Sift	Benign	0.14	T;T;T
Sift4G	Uncertain	0.013	D;D;D
Vest4		0.38
MutPred		0.56		Gain of ubiquitination at K1221 (P = 0.0561);.;.;
MVP		0.85
MPC		0.54
ClinPred		0.26	T
GERP RS		1.9
Varity_R		0.075
gMVP		0.27

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-44555743;