Variant 19-33204849-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_002333.4(LRP3):c.472C>G(p.Arg158Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

LRP3
NM_002333.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.735

Variant links:

Genes affected

LRP3 (HGNC:6695): (LDL receptor related protein 3) Involved in negative regulation of fat cell differentiation; positive regulation of osteoblast differentiation; and regulation of gene expression. Predicted to be located in clathrin-coated pit. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

LRP3 links:

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ACMG classification

Classification made for transcript

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, 0.793

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP3	NM_002333.4 link	c.472C>G	p.Arg158Gly	missense_variant	4/7	ENST00000253193.9	NP_002324.2	O75074
LRP3	XM_005258945.2 link	c.472C>G	p.Arg158Gly	missense_variant	4/7		XP_005259002.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LRP3	ENST00000253193.9 link	c.472C>G	p.Arg158Gly	missense_variant	4/7	1	NM_002333.4	ENSP00000253193.6	O75074
LRP3	ENST00000592484.5 link	c.226C>G	p.Arg76Gly	missense_variant	4/5	4		ENSP00000476735.1	V9GYG8
LRP3	ENST00000590275.1 link	n.393C>G		non_coding_transcript_exon_variant	3/3	2
LRP3	ENST00000590278.1 link	n.980C>G		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250270

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135378

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460474

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726666

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

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

May 23, 2023

The c.472C>G (p.R158G) alteration is located in exon 4 (coding exon 4) of the LRP3 gene. This alteration results from a C to G substitution at nucleotide position 472, causing the arginine (R) at amino acid position 158 to be replaced by a glycine (G). 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

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.088

.;T

Eigen

Benign

0.16

Eigen_PC

Benign

0.088

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.91

D;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.79

D;D

MetaSVM

Uncertain

0.066

MutationAssessor

Uncertain

2.1

.;M

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.5

.;D

REVEL

Pathogenic

0.70

Sift

Benign

0.030

.;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.98

.;D

Vest4

0.90

MutPred

0.64

.;Loss of stability (P = 0.0143);

MVP

0.89

MPC

1.0

ClinPred

0.94

GERP RS

2.7

Varity_R

0.52

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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