rs12285364

Variant names:

• chr11-121522517-C-T
• rs12285364
• NM_003105.6:c.1405-69C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08
• Publications: 24 publications found

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

ACMG classification

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.

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.1405-69C>T		intron	N/A	NP_003096.2	Q92673

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	ENST00000260197.12	TSL:1 MANE Select	c.1405-69C>T		intron	N/A	ENSP00000260197.6	Q92673
	SORL1	ENST00000532451.1	TSL:1	n.1357-69C>T		intron	N/A
	SORL1	ENST00000905166.1		c.1405-69C>T		intron	N/A	ENSP00000575225.1

Frequencies

GnomAD3 genomes AF: 0.0685 AC: 10418 AN: 152124 Hom.: 435 Cov.: 32

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

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

GnomAD4 genome AF: 0.0685 AC: 10425 AN: 152242 Hom.: 436 Cov.: 32 AF XY: 0.0699 AC XY: 5201 AN XY: 74428

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: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0452 AC: 3072 AN: 68014

Other (OTH) AF: 0.0662 AC: 140 AN: 2114

Alfa AF: 0.0598 Hom.: 46

Bravo AF: 0.0727

Asia WGS AF: 0.113 AC: 392 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.22
DANN	Benign	0.76
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12285364; hg19: chr11-121393226;