7-44515928-A-T

Variant names:

• chr7-44515928-A-T
• NM_001101648.2:c.3671T>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001101648.2(NPC1L1):​c.3671T>A​(p.Ile1224Asn) 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. 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: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.65

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1L1	NM_001101648.2	c.3671T>A	p.Ile1224Asn	missense_variant	Exon 18 of 19	ENST00000381160.8	NP_001095118.1
NPC1L1	NM_013389.3	c.3752T>A	p.Ile1251Asn	missense_variant	Exon 19 of 20		NP_037521.2
NPC1L1	XM_011515326.4	c.3476T>A	p.Ile1159Asn	missense_variant	Exon 17 of 18		XP_011513628.1
NPC1L1	XM_011515328.3	c.2030T>A	p.Ile677Asn	missense_variant	Exon 15 of 16		XP_011513630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1L1	ENST00000381160.8	c.3671T>A	p.Ile1224Asn	missense_variant	Exon 18 of 19	1	NM_001101648.2	ENSP00000370552.3
NPC1L1	ENST00000289547.8	c.3752T>A	p.Ile1251Asn	missense_variant	Exon 19 of 20	1		ENSP00000289547.4
NPC1L1	ENST00000546276.5	c.3533T>A	p.Ile1178Asn	missense_variant	Exon 17 of 18	1		ENSP00000438033.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3752T>A (p.I1251N) alteration is located in exon 19 (coding exon 19) of the NPC1L1 gene. This alteration results from a T to A substitution at nucleotide position 3752, causing the isoleucine (I) at amino acid position 1251 to be replaced by an asparagine (N). 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	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;T;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.4	M;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.3	D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.91
MutPred		0.70		Loss of stability (P = 0.0189);.;.;
MVP		0.99
MPC		0.87
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.89
gMVP		0.96

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: chr7-44555527;