7-44517235-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001101648.2(NPC1L1):c.3259G>C(p.Asp1087His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,613,954 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1087E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0074 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (10 hom.)
• Consequence: NPC1L1 NM_001101648.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.67

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008909345).
• BP6: Variant 7-44517235-C-G is Benign according to our data. Variant chr7-44517235-C-G is described in ClinVar as [Benign]. Clinvar id is 778302.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00736 (1120/152100) while in subpopulation AFR AF= 0.0257 (1067/41492). AF 95% confidence interval is 0.0244. There are 13 homozygotes in gnomad4. There are 539 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1L1	NM_001101648.2	c.3259G>C	p.Asp1087His	missense_variant	15/19	ENST00000381160.8
NPC1L1	NM_013389.3	c.3340G>C	p.Asp1114His	missense_variant	16/20
NPC1L1	XM_011515326.4	c.3064G>C	p.Asp1022His	missense_variant	14/18
NPC1L1	XM_011515328.3	c.1618G>C	p.Asp540His	missense_variant	12/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1L1	ENST00000381160.8	c.3259G>C	p.Asp1087His	missense_variant	15/19	1	NM_001101648.2	P1
NPC1L1	ENST00000289547.8	c.3340G>C	p.Asp1114His	missense_variant	16/20	1
NPC1L1	ENST00000546276.5	c.3121G>C	p.Asp1041His	missense_variant	14/18	1

Frequencies

GnomAD3 genomes AF: 0.00732 AC: 1113 AN: 151982 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00645

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00202 AC: 507 AN: 251424 Hom.: 5 AF XY: 0.00141 AC XY: 192 AN XY: 135880

Gnomad AFR exome AF: 0.0277

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000811 AC: 1186 AN: 1461854 Hom.: 10 Cov.: 32 AF XY: 0.000663 AC XY: 482 AN XY: 727216

Gnomad4 AFR exome AF: 0.0300

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00146

GnomAD4 genome AF: 0.00736 AC: 1120 AN: 152100 Hom.: 13 Cov.: 32 AF XY: 0.00725 AC XY: 539 AN XY: 74358

Gnomad4 AFR AF: 0.0257

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000428 Hom.: 0

Bravo AF: 0.00835

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0234 AC: 103

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00241 AC: 292

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.25	T;T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.91	D;D;D
MetaRNN	Benign	0.0089	T;T;T
MetaSVM	Uncertain	-0.023	T
MutationAssessor	Benign	1.9	L;.;.
MutationTaster	Benign	0.91	D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Uncertain	0.41
Sift	Benign	0.065	T;T;T
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.54
MVP		0.90
MPC		0.69
ClinPred		0.024	T
GERP RS		5.3
Varity_R		0.14
gMVP		0.53

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

LitVar

Other links and lift over

dbSNP: rs79519744; hg19: chr7-44556834;