12-57196975-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002332.3(LRP1):c.8893-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,602,714 control chromosomes in the GnomAD database, including 90,575 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 11790 hom., cov: 33)

Exomes 𝑓: 0.32 ( 78785 hom. )

Consequence

LRP1
NM_002332.3 splice_region, intron

Scores

Splicing: ADA: 0.0002673

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.664

Publications

16 publications found

Variant links:

Genes affected

LRP1 (HGNC:6692): (LDL receptor related protein 1) This gene encodes a member of the low-density lipoprotein receptor family of proteins. The encoded preproprotein is proteolytically processed by furin to generate 515 kDa and 85 kDa subunits that form the mature receptor (PMID: 8546712). This receptor is involved in several cellular processes, including intracellular signaling, lipid homeostasis, and clearance of apoptotic cells. In addition, the encoded protein is necessary for the alpha 2-macroglobulin-mediated clearance of secreted amyloid precursor protein and beta-amyloid, the main component of amyloid plaques found in Alzheimer patients. Expression of this gene decreases with age and has been found to be lower than controls in brain tissue from Alzheimer's disease patients. [provided by RefSeq, Oct 2015]

LRP1 Gene-Disease associations (from GenCC):

keratosis follicularis spinulosa decalvans
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
atrophoderma vermiculata
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
developmental dysplasia of the hip 3
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
keratosis pilaris atrophicans
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
schizophrenia
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

LRP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 12-57196975-C-T is Benign according to our data. Variant chr12-57196975-C-T is described in ClinVar as Benign. ClinVar VariationId is 1252707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP1	NM_002332.3 link	c.8893-7C>T		splice_region_variant, intron_variant	Intron 55 of 88	ENST00000243077.8	NP_002323.2	Q07954-1Q59FG2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP1	ENST00000243077.8 link	c.8893-7C>T		splice_region_variant, intron_variant	Intron 55 of 88	1	NM_002332.3	ENSP00000243077.3		Q07954-1

Frequencies

GnomAD3 genomes

AF:

0.383

AC:

58135

AN:

151856

Hom.:

11763

Cov.:

show subpopulations

Gnomad AFR

AF:

0.501

Gnomad AMI

AF:

0.429

Gnomad AMR

AF:

0.395

Gnomad ASJ

AF:

0.322

Gnomad EAS

AF:

0.458

Gnomad SAS

AF:

0.233

Gnomad FIN

AF:

0.393

Gnomad MID

AF:

0.335

Gnomad NFE

AF:

0.315

Gnomad OTH

AF:

0.372

GnomAD2 exomes

AF:

0.358

AC:

83732

AN:

234050

AF XY:

0.338

show subpopulations

Gnomad AFR exome

AF:

0.506

Gnomad AMR exome

AF:

0.511

Gnomad ASJ exome

AF:

0.317

Gnomad EAS exome

AF:

0.445

Gnomad FIN exome

AF:

0.402

Gnomad NFE exome

AF:

0.314

Gnomad OTH exome

AF:

0.336

GnomAD4 exome

AF:

0.323

AC:

468837

AN:

1450740

Hom.:

78785

Cov.:

AF XY:

0.317

AC XY:

229035

AN XY:

721810

show subpopulations

African (AFR)

AF:

0.509

AC:

16982

AN:

33336

American (AMR)

AF:

0.500

AC:

21699

AN:

43432

Ashkenazi Jewish (ASJ)

AF:

0.316

AC:

8215

AN:

25998

East Asian (EAS)

AF:

0.409

AC:

16071

AN:

39332

South Asian (SAS)

AF:

0.212

AC:

18210

AN:

85750

European-Finnish (FIN)

AF:

0.398

AC:

19511

AN:

48976

Middle Eastern (MID)

AF:

0.325

AC:

1789

AN:

5512

European-Non Finnish (NFE)

AF:

0.313

AC:

346422

AN:

1108366

Other (OTH)

AF:

0.332

AC:

19938

AN:

60038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

14045

28090

42136

56181

70226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11490

22980

34470

45960

57450

<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:

0.383

AC:

58210

AN:

151974

Hom.:

11790

Cov.:

AF XY:

0.382

AC XY:

28396

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.501

AC:

20761

AN:

41438

American (AMR)

AF:

0.396

AC:

6045

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.322

AC:

1116

AN:

3470

East Asian (EAS)

AF:

0.457

AC:

2348

AN:

5138

South Asian (SAS)

AF:

0.232

AC:

1120

AN:

4818

European-Finnish (FIN)

AF:

0.393

AC:

4161

AN:

10580

Middle Eastern (MID)

AF:

0.330

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.315

AC:

21391

AN:

67948

Other (OTH)

AF:

0.371

AC:

781

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1799

3597

5396

7194

8993

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

546

1092

1638

2184

2730

<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:

0.344

Hom.:

4508

Bravo

AF:

0.400

Asia WGS

AF:

0.412

AC:

1431

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Keratosis pilaris

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

2.5

(source)

DANN

Benign

0.87

PhyloP100

0.66

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00027

dbscSNV1_RF

Benign

0.0

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over