dbSNP rs3781835: SORL1:c.3580+145G>A (chr11-121577545-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.3580+145G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.021 in 880,738 control chromosomes in the GnomAD database, including 363 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 ( 102 hom., cov: 33)

Exomes 𝑓: 0.019 ( 261 hom. )

Consequence

SORL1
NM_003105.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.417

Publications

14 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=-0.83).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6 link	c.3580+145G>A		intron_variant	Intron 25 of 47	ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
SORL1	ENST00000260197.12 link	c.3580+145G>A	intron_variant	Intron 25 of 47	1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000525532.5 link	c.412+145G>A	intron_variant	Intron 5 of 27	2		ENSP00000434634.1
SORL1	ENST00000534286.5 link	c.310+145G>A	intron_variant	Intron 2 of 24	2		ENSP00000436447.1
SORL1	ENST00000532694.5 link	c.118+145G>A	intron_variant	Intron 2 of 24	2		ENSP00000432131.1

Frequencies

GnomAD3 genomes

AF:

0.0301

AC:

4582

AN:

152156

Hom.:

102

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0573

Gnomad AMI

AF:

0.00549

Gnomad AMR

AF:

0.0220

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.0767

Gnomad SAS

AF:

0.0213

Gnomad FIN

AF:

0.00792

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0174

Gnomad OTH

AF:

0.0239

GnomAD4 exome

AF:

0.0191

AC:

13888

AN:

728464

Hom.:

261

AF XY:

0.0190

AC XY:

6930

AN XY:

364912

show subpopulations

African (AFR)

AF:

0.0573

AC:

980

AN:

17092

American (AMR)

AF:

0.0111

AC:

190

AN:

17134

Ashkenazi Jewish (ASJ)

AF:

0.0116

AC:

157

AN:

13524

East Asian (EAS)

AF:

0.0900

AC:

2666

AN:

29612

South Asian (SAS)

AF:

0.0203

AC:

692

AN:

34080

European-Finnish (FIN)

AF:

0.00815

AC:

319

AN:

39126

Middle Eastern (MID)

AF:

0.0219

AC:

AN:

3874

European-Non Finnish (NFE)

AF:

0.0151

AC:

8190

AN:

540802

Other (OTH)

AF:

0.0183

AC:

609

AN:

33220

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

656

1313

1969

2626

3282

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

298

596

894

1192

1490

<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:

0.0301

AC:

4584

AN:

152274

Hom.:

102

Cov.:

AF XY:

0.0292

AC XY:

2176

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0572

AC:

2376

AN:

41548

American (AMR)

AF:

0.0220

AC:

337

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3468

East Asian (EAS)

AF:

0.0770

AC:

399

AN:

5180

South Asian (SAS)

AF:

0.0214

AC:

103

AN:

4824

European-Finnish (FIN)

AF:

0.00792

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0174

AC:

1184

AN:

68016

Other (OTH)

AF:

0.0236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

228

457

685

914

1142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.0224

Hom.:

Bravo

AF:

0.0324

Asia WGS

AF:

0.0460

AC:

162

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.41

(source)

DANN

Benign

0.72

PhyloP100

-0.42

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

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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