Genetic Variant LRP8:c.*955C>G (chr1-53246063-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004631.5(LRP8):c.*955C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 152,030 control chromosomes in the GnomAD database, including 9,149 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.32 ( 9148 hom., cov: 32)

Exomes 𝑓: 0.30 ( 1 hom. )

Consequence

LRP8
NM_004631.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.659

Publications

27 publications found

Variant links:

Genes affected

LRP8 (HGNC:6700): (LDL receptor related protein 8) This gene encodes a member of the low density lipoprotein receptor (LDLR) family. Low density lipoprotein receptors are cell surface proteins that play roles in both signal transduction and receptor-mediated endocytosis of specific ligands for lysosomal degradation. The encoded protein plays a critical role in the migration of neurons during development by mediating Reelin signaling, and also functions as a receptor for the cholesterol transport protein apolipoprotein E. Expression of this gene may be a marker for major depressive disorder. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jun 2011]

LRP8 links:

MAGOH-DT (HGNC:49539): (MAGOH divergent transcript)

MAGOH-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.472 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
LRP8	NM_004631.5 link	c.*955C>G	3_prime_UTR_variant	Exon 19 of 19	ENST00000306052.12	NP_004622.2
LRP8	NM_001018054.3 link	c.*955C>G	3_prime_UTR_variant	Exon 18 of 18		NP_001018064.1
LRP8	NM_033300.4 link	c.*955C>G	3_prime_UTR_variant	Exon 17 of 17		NP_150643.2
LRP8	NM_017522.5 link	c.*955C>G	3_prime_UTR_variant	Exon 16 of 16		NP_059992.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP8	ENST00000306052.12 link	c.*955C>G		3_prime_UTR_variant	Exon 19 of 19	1	NM_004631.5	ENSP00000303634.6

Frequencies

GnomAD3 genomes

AF:

0.318

AC:

48279

AN:

151902

Hom.:

9143

Cov.:

show subpopulations

Gnomad AFR

AF:

0.120

Gnomad AMI

AF:

0.502

Gnomad AMR

AF:

0.314

Gnomad ASJ

AF:

0.315

Gnomad EAS

AF:

0.488

Gnomad SAS

AF:

0.199

Gnomad FIN

AF:

0.447

Gnomad MID

AF:

0.237

Gnomad NFE

AF:

0.413

Gnomad OTH

AF:

0.295

GnomAD4 exome

AF:

0.300

AC:

AN:

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.167

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.500

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.825

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.318

AC:

48289

AN:

152020

Hom.:

9148

Cov.:

AF XY:

0.317

AC XY:

23547

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.120

AC:

4986

AN:

41512

American (AMR)

AF:

0.314

AC:

4800

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.315

AC:

1094

AN:

3472

East Asian (EAS)

AF:

0.488

AC:

2519

AN:

5162

South Asian (SAS)

AF:

0.198

AC:

956

AN:

4820

European-Finnish (FIN)

AF:

0.447

AC:

4709

AN:

10536

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.413

AC:

28071

AN:

67924

Other (OTH)

AF:

0.300

AC:

634

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1560

3120

4681

6241

7801

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

480

960

1440

1920

2400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.251

Hom.:

758

Bravo

AF:

0.302

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

2.3

(source)

DANN

Benign

0.42

PhyloP100

0.66

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over