Variant chr2-140239517-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018557.3(LRP1B):c.13340T>C(p.Ile4447Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,602,452 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LRP1B
NM_018557.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.36

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LRP1B	NM_018557.3 linkuse as main transcript	c.13340T>C	p.Ile4447Thr	missense_variant	88/91	ENST00000389484.8
LRP1B	XM_017004341.2 linkuse as main transcript	c.12950T>C	p.Ile4317Thr	missense_variant	88/91
LRP1B	XM_017004342.1 linkuse as main transcript	c.8192T>C	p.Ile2731Thr	missense_variant	59/62

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
LRP1B	ENST00000389484.8 linkuse as main transcript	c.13340T>C	p.Ile4447Thr	missense_variant	88/91	1	NM_018557.3	P1
LRP1B	ENST00000437977.5 linkuse as main transcript	c.2036T>C	p.Ile679Thr	missense_variant	15/17	5
LRP1B	ENST00000442974.1 linkuse as main transcript	c.650T>C	p.Ile217Thr	missense_variant	6/7	5

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

150824

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1451628

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722374

show subpopulations

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:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000133

AC:

AN:

150824

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73624

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.13340T>C (p.I4447T) alteration is located in exon 88 (coding exon 88) of the LRP1B gene. This alteration results from a T to C substitution at nucleotide position 13340, causing the isoleucine (I) at amino acid position 4447 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.19

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.047

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.015

MetaRNN

Uncertain

0.73

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

0.97

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.66

REVEL

Benign

0.28

Sift

Uncertain

0.025

Sift4G

Uncertain

0.0080

Polyphen

0.76

Vest4

0.90

MutPred

0.56

Loss of catalytic residue at P4449 (P = 0.0713);

MVP

0.093

MPC

0.30

ClinPred

0.80

GERP RS

4.3

Varity_R

0.13

gMVP

0.70

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