Genetic Variant LRP1B:p.Asn4559Ser (chr2-140233310-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_018557.3(LRP1B):c.13676A>G(p.Asn4559Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,589,746 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 2 hom. )

Consequence

LRP1B
NM_018557.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.67

Variant links:

Genes affected

LRP1B (HGNC:6693): (LDL receptor related protein 1B) This gene encodes a member of the low density lipoprotein (LDL) receptor family. These receptors play a wide variety of roles in normal cell function and development due to their interactions with multiple ligands. Disruption of this gene has been reported in several types of cancer. [provided by RefSeq, Jun 2016]

LRP1B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.049071103).

BP6

Variant 2-140233310-T-C is Benign according to our data. Variant chr2-140233310-T-C is described in ClinVar as [Benign]. Clinvar id is 3770607.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00139 (210/151168) while in subpopulation NFE AF= 0.0025 (169/67492). AF 95% confidence interval is 0.0022. There are 0 homozygotes in gnomad4. There are 103 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 210 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP1B	NM_018557.3 link	c.13676A>G	p.Asn4559Ser	missense_variant	Exon 91 of 91	ENST00000389484.8	NP_061027.2	Q9NZR2
LRP1B	XM_017004341.2 link	c.13286A>G	p.Asn4429Ser	missense_variant	Exon 91 of 91		XP_016859830.1
LRP1B	XM_017004342.1 link	c.8528A>G	p.Asn2843Ser	missense_variant	Exon 62 of 62		XP_016859831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP1B	ENST00000389484.8 link	c.13676A>G	p.Asn4559Ser	missense_variant	Exon 91 of 91	1	NM_018557.3	ENSP00000374135.3		Q9NZR2
LRP1B	ENST00000437977.5 link	c.2270A>G	p.Asn757Ser	missense_variant	Exon 17 of 17	5		ENSP00000415052.1		H0Y7T7

Frequencies

GnomAD3 genomes

AF:

0.00139

AC:

210

AN:

151168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000460

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000398

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00250

Gnomad OTH

AF:

0.000484

GnomAD3 exomes

AF:

0.00173

AC:

411

AN:

236896

Hom.:

AF XY:

0.00158

AC XY:

203

AN XY:

128172

show subpopulations

Gnomad AFR exome

AF:

0.000257

Gnomad AMR exome

AF:

0.000732

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00156

Gnomad NFE exome

AF:

0.00312

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00204

AC:

2941

AN:

1438578

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

1366

AN XY:

715474

show subpopulations

Gnomad4 AFR exome

AF:

0.000217

Gnomad4 AMR exome

AF:

0.000641

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000122

Gnomad4 FIN exome

AF:

0.00192

Gnomad4 NFE exome

AF:

0.00243

Gnomad4 OTH exome

AF:

0.00213

GnomAD4 genome

AF:

0.00139

AC:

210

AN:

151168

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

103

AN XY:

73774

show subpopulations

Gnomad4 AFR

AF:

0.000460

Gnomad4 AMR

AF:

0.000398

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00141

Gnomad4 NFE

AF:

0.00250

Gnomad4 OTH

AF:

0.000484

Alfa

AF:

0.00202

Hom.:

Bravo

AF:

0.00135

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00206

AC:

250

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LRP1B: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.088

MetaRNN

Benign

0.049

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.1

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.8

REVEL

Benign

0.28

Sift

Uncertain

0.013

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.69

MVP

0.43

MPC

0.26

ClinPred

0.045

GERP RS

5.7

Varity_R

0.18

gMVP

0.68

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over