dbSNP rs12285364: SORL1:c.1405-69C>T (chr11-121522517-C-T) – 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.1405-69C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0591 in 1,201,920 control chromosomes in the GnomAD database, including 2,727 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 0.068 ( 436 hom., cov: 32)

Exomes 𝑓: 0.058 ( 2291 hom. )

Consequence

SORL1
NM_003105.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.08

Publications

24 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=-0.82).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6 link	c.1405-69C>T		intron_variant	Intron 9 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.1405-69C>T		intron_variant	Intron 9 of 47	1	NM_003105.6	ENSP00000260197.6		Q92673
SORL1	ENST00000532451.1 link	n.1357-69C>T		intron_variant	Intron 9 of 14	1

Frequencies

GnomAD3 genomes

AF:

0.0685

AC:

10418

AN:

152124

Hom.:

435

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0966

Gnomad AMI

AF:

0.0615

Gnomad AMR

AF:

0.0887

Gnomad ASJ

AF:

0.0326

Gnomad EAS

AF:

0.125

Gnomad SAS

AF:

0.116

Gnomad FIN

AF:

0.0437

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0451

Gnomad OTH

AF:

0.0669

GnomAD4 exome

AF:

0.0577

AC:

60558

AN:

1049678

Hom.:

2291

AF XY:

0.0589

AC XY:

31780

AN XY:

539750

show subpopulations

African (AFR)

AF:

0.0975

AC:

2480

AN:

25428

American (AMR)

AF:

0.111

AC:

4853

AN:

43838

Ashkenazi Jewish (ASJ)

AF:

0.0324

AC:

745

AN:

23006

East Asian (EAS)

AF:

0.140

AC:

5272

AN:

37662

South Asian (SAS)

AF:

0.106

AC:

8155

AN:

77234

European-Finnish (FIN)

AF:

0.0444

AC:

2186

AN:

49268

Middle Eastern (MID)

AF:

0.0374

AC:

185

AN:

4946

European-Non Finnish (NFE)

AF:

0.0457

AC:

33907

AN:

741458

Other (OTH)

AF:

0.0592

AC:

2775

AN:

46838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

2988

5976

8963

11951

14939

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1162

2324

3486

4648

5810

<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:

0.0685

AC:

10425

AN:

152242

Hom.:

436

Cov.:

AF XY:

0.0699

AC XY:

5201

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0964

AC:

4006

AN:

41542

American (AMR)

AF:

0.0887

AC:

1357

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0326

AC:

113

AN:

3470

East Asian (EAS)

AF:

0.125

AC:

649

AN:

5176

South Asian (SAS)

AF:

0.116

AC:

558

AN:

4816

European-Finnish (FIN)

AF:

0.0437

AC:

463

AN:

10604

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0452

AC:

3072

AN:

68014

Other (OTH)

AF:

0.0662

AC:

140

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

487

974

1460

1947

2434

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

240

360

480

600

<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:

0.0598

Hom.:

Bravo

AF:

0.0727

Asia WGS

AF:

0.113

AC:

392

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.22

(source)

DANN

Benign

0.76

PhyloP100

-1.1

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