rs895973476

Variant names:

• chr7-44516768-T-A
• rs895973476
• NM_001101648.2:c.3454A>T

Your query was ambiguous. Multiple possible variants found:

• chr7-44516768-T-A
• chr7-44516768-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001101648.2(NPC1L1):​c.3454A>T​(p.Thr1152Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1152A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NPC1L1 NM_001101648.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.48
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

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.3454A>T	p.Thr1152Ser	missense	Exon 16 of 19	NP_001095118.1	A0A0C4DFX6
	NPC1L1	NM_013389.3		c.3535A>T	p.Thr1179Ser	missense	Exon 17 of 20	NP_037521.2	Q9UHC9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPC1L1	ENST00000381160.8	TSL:1 MANE Select	c.3454A>T	p.Thr1152Ser	missense	Exon 16 of 19	ENSP00000370552.3	A0A0C4DFX6
	NPC1L1	ENST00000289547.8	TSL:1	c.3535A>T	p.Thr1179Ser	missense	Exon 17 of 20	ENSP00000289547.4	Q9UHC9-1
	NPC1L1	ENST00000546276.5	TSL:1	c.3316A>T	p.Thr1106Ser	missense	Exon 15 of 18	ENSP00000438033.1	A0A0C4DGG6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461660 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727102

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111926

Other (OTH) AF: 0.0000166 AC: 1 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.5
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.75
Sift	Benign	0.052	T
Sift4G	Uncertain	0.035	D
Vest4		0.62
MutPred		0.63		Loss of catalytic residue at T1179 (P = 0.2899)
MVP		0.96
MPC		0.62
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.22
gMVP		0.52
Mutation Taster		=67/33	polymorphism

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: rs895973476; hg19: chr7-44556367;