chr7-44516768-T-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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.

• 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

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 3 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1L1	NM_001101648.2	c.3454A>T	p.Thr1152Ser	missense_variant	Exon 16 of 19	ENST00000381160.8	NP_001095118.1
NPC1L1	NM_013389.3	c.3535A>T	p.Thr1179Ser	missense_variant	Exon 17 of 20		NP_037521.2
NPC1L1	XM_011515326.4	c.3259A>T	p.Thr1087Ser	missense_variant	Exon 15 of 18		XP_011513628.1
NPC1L1	XM_011515328.3	c.1813A>T	p.Thr605Ser	missense_variant	Exon 13 of 16		XP_011513630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1L1	ENST00000381160.8	c.3454A>T	p.Thr1152Ser	missense_variant	Exon 16 of 19	1	NM_001101648.2	ENSP00000370552.3
NPC1L1	ENST00000289547.8	c.3535A>T	p.Thr1179Ser	missense_variant	Exon 17 of 20	1		ENSP00000289547.4
NPC1L1	ENST00000546276.5	c.3316A>T	p.Thr1106Ser	missense_variant	Exon 15 of 18	1		ENSP00000438033.1

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

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;T;T
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.4	M;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Pathogenic	0.75
Sift	Benign	0.052	T;D;D
Sift4G	Uncertain	0.035	D;D;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

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: chr7-44556367;