dbSNP rs2298814: SORL1:c.2439+64G>A (chr11-121554173-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_003105.6(SORL1):c.2439+64G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,463,470 control chromosomes in the GnomAD database, including 478 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 0.030 ( 97 hom., cov: 33)

Exomes 𝑓: 0.019 ( 381 hom. )

Consequence

SORL1
NM_003105.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.489

Publications

7 publications found

Variant links:

Genes affected

SORL1 (HGNC:11185): (sortilin related receptor 1) This gene encodes a mosaic protein that belongs to at least two families: the vacuolar protein sorting 10 (VPS10) domain-containing receptor family, and the low density lipoprotein receptor (LDLR) family. The encoded protein also contains fibronectin type III repeats and an epidermal growth factor repeat. The encoded preproprotein is proteolytically processed to generate the mature receptor, which likely plays roles in endocytosis and sorting. Mutations in this gene may be associated with Alzheimer's disease. [provided by RefSeq, Feb 2016]

SORL1 Gene-Disease associations (from GenCC):

early-onset autosomal dominant Alzheimer disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SORL1 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 = 0.0749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6 link	c.2439+64G>A		intron_variant	Intron 17 of 47	ENST00000260197.12	NP_003096.2	Q92673A0A024R3H2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12 link	c.2439+64G>A		intron_variant	Intron 17 of 47	1	NM_003105.6	ENSP00000260197.6		Q92673

Frequencies

GnomAD3 genomes

AF:

0.0300

AC:

4562

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0565

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0217

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.0809

Gnomad SAS

AF:

0.0217

Gnomad FIN

AF:

0.00791

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0174

Gnomad OTH

AF:

0.0206

GnomAD4 exome

AF:

0.0195

AC:

25513

AN:

1311154

Hom.:

381

AF XY:

0.0194

AC XY:

12610

AN XY:

650122

show subpopulations

African (AFR)

AF:

0.0590

AC:

1782

AN:

30222

American (AMR)

AF:

0.0109

AC:

398

AN:

36652

Ashkenazi Jewish (ASJ)

AF:

0.0116

AC:

260

AN:

22474

East Asian (EAS)

AF:

0.0879

AC:

3339

AN:

37982

South Asian (SAS)

AF:

0.0212

AC:

1629

AN:

76710

European-Finnish (FIN)

AF:

0.00818

AC:

420

AN:

51372

Middle Eastern (MID)

AF:

0.0208

AC:

108

AN:

5202

European-Non Finnish (NFE)

AF:

0.0166

AC:

16478

AN:

995524

Other (OTH)

AF:

0.0200

AC:

1099

AN:

55016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1212

2424

3636

4848

6060

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

680

1360

2040

2720

3400

<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:

0.0300

AC:

4566

AN:

152316

Hom.:

Cov.:

AF XY:

0.0292

AC XY:

2178

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0564

AC:

2344

AN:

41558

American (AMR)

AF:

0.0216

AC:

331

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3470

East Asian (EAS)

AF:

0.0813

AC:

422

AN:

5192

South Asian (SAS)

AF:

0.0217

AC:

105

AN:

4830

European-Finnish (FIN)

AF:

0.00791

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0174

AC:

1186

AN:

68018

Other (OTH)

AF:

0.0203

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

228

456

683

911

1139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0288

Hom.:

Bravo

AF:

0.0324

Asia WGS

AF:

0.0480

AC:

167

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.0

(source)

DANN

Benign

0.74

PhyloP100

-0.49

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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