dbSNP rs560573: SORL1:c.758+65T>A (chr11-121490175-T-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.758+65T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 1,133,190 control chromosomes in the GnomAD database, including 88,946 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 0.37 ( 10770 hom., cov: 32)

Exomes 𝑓: 0.40 ( 78176 hom. )

Consequence

SORL1
NM_003105.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.978

Publications

13 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=-0.93).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003105.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	NM_003105.6	MANE Select	c.758+65T>A		intron	N/A	NP_003096.2	Q92673

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SORL1	ENST00000260197.12	TSL:1 MANE Select	c.758+65T>A	intron	N/A	ENSP00000260197.6	Q92673
SORL1	ENST00000532451.1	TSL:1	n.710+65T>A	intron	N/A
SORL1	ENST00000905166.1		c.758+65T>A	intron	N/A	ENSP00000575225.1

Frequencies

GnomAD3 genomes

AF:

0.370

AC:

56176

AN:

151880

Hom.:

10749

Cov.:

show subpopulations

Gnomad AFR

AF:

0.302

Gnomad AMI

AF:

0.249

Gnomad AMR

AF:

0.324

Gnomad ASJ

AF:

0.273

Gnomad EAS

AF:

0.550

Gnomad SAS

AF:

0.445

Gnomad FIN

AF:

0.459

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.396

Gnomad OTH

AF:

0.354

GnomAD4 exome

AF:

0.397

AC:

389103

AN:

981192

Hom.:

78176

AF XY:

0.398

AC XY:

202250

AN XY:

507652

show subpopulations

African (AFR)

AF:

0.302

AC:

7265

AN:

24096

American (AMR)

AF:

0.365

AC:

15648

AN:

42860

Ashkenazi Jewish (ASJ)

AF:

0.282

AC:

6449

AN:

22894

East Asian (EAS)

AF:

0.522

AC:

19423

AN:

37178

South Asian (SAS)

AF:

0.437

AC:

33108

AN:

75696

European-Finnish (FIN)

AF:

0.443

AC:

23340

AN:

52648

Middle Eastern (MID)

AF:

0.311

AC:

1509

AN:

4848

European-Non Finnish (NFE)

AF:

0.392

AC:

265291

AN:

676444

Other (OTH)

AF:

0.383

AC:

17070

AN:

44528

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

11276

22552

33829

45105

56381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6434

12868

19302

25736

32170

<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:

0.370

AC:

56228

AN:

151998

Hom.:

10770

Cov.:

AF XY:

0.372

AC XY:

27608

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.302

AC:

12505

AN:

41450

American (AMR)

AF:

0.325

AC:

4964

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.273

AC:

949

AN:

3472

East Asian (EAS)

AF:

0.549

AC:

2841

AN:

5174

South Asian (SAS)

AF:

0.444

AC:

2135

AN:

4810

European-Finnish (FIN)

AF:

0.459

AC:

4842

AN:

10540

Middle Eastern (MID)

AF:

0.248

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.396

AC:

26930

AN:

67968

Other (OTH)

AF:

0.361

AC:

762

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

1824

3648

5471

7295

9119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

572

1144

1716

2288

2860

<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:

0.377

Hom.:

1355

Bravo

AF:

0.357

Asia WGS

AF:

0.498

AC:

1733

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.035

(source)

DANN

Benign

0.74

PhyloP100

-0.98

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over