7-44516910-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Moderate BP6_Moderate

The NM_001101648.2(NPC1L1):c.3312G>C(p.Gln1104His) variant causes a missense change. The variant allele was found at a frequency of 0.000305 in 1,613,760 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (3 hom.)
• Consequence: NPC1L1 NM_001101648.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.70

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11469075).
• BP6: Variant 7-44516910-C-G is Benign according to our data. Variant chr7-44516910-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 745816.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1L1	NM_001101648.2	c.3312G>C	p.Gln1104His	missense_variant	16/19	ENST00000381160.8
NPC1L1	NM_013389.3	c.3393G>C	p.Gln1131His	missense_variant	17/20
NPC1L1	XM_011515326.4	c.3117G>C	p.Gln1039His	missense_variant	15/18
NPC1L1	XM_011515328.3	c.1671G>C	p.Gln557His	missense_variant	13/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1L1	ENST00000381160.8	c.3312G>C	p.Gln1104His	missense_variant	16/19	1	NM_001101648.2	P1
NPC1L1	ENST00000289547.8	c.3393G>C	p.Gln1131His	missense_variant	17/20	1
NPC1L1	ENST00000546276.5	c.3174G>C	p.Gln1058His	missense_variant	15/18	1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00365

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000220 AC: 55 AN: 249636 Hom.: 0 AF XY: 0.000193 AC XY: 26 AN XY: 134982

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00272

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000322 AC: 471 AN: 1461434 Hom.: 3 Cov.: 32 AF XY: 0.000282 AC XY: 205 AN XY: 727010

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0111

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.000174 AC XY: 13 AN XY: 74504

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00366

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000259 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.000305 AC: 37

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

May 25, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	3.5	M;.;.
MutationTaster	Benign	0.95	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.88
MutPred		0.61		Loss of catalytic residue at Q1131 (P = 0.0575);.;.;
MVP		0.97
MPC		0.63
ClinPred		0.42	T
GERP RS		2.7
Varity_R		0.81
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs116716160; hg19: chr7-44556509; COSMIC: COSV56923179;