rs12285364

Positions:

• chr11-121522517-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
SORL1	NM_003105.6	c.1405-69C>T		intron_variant		ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.1405-69C>T		intron_variant		1	NM_003105.6	ENSP00000260197	P1
SORL1	ENST00000532451.1	n.1357-69C>T		intron_variant, non_coding_transcript_variant		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

Gnomad4 AFR exome AF: 0.0975

Gnomad4 AMR exome AF: 0.111

Gnomad4 ASJ exome AF: 0.0324

Gnomad4 EAS exome AF: 0.140

Gnomad4 SAS exome AF: 0.106

Gnomad4 FIN exome AF: 0.0444

Gnomad4 NFE exome AF: 0.0457

Gnomad4 OTH exome AF: 0.0592

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

Gnomad4 AFR AF: 0.0964

Gnomad4 AMR AF: 0.0887

Gnomad4 ASJ AF: 0.0326

Gnomad4 EAS AF: 0.125

Gnomad4 SAS AF: 0.116

Gnomad4 FIN AF: 0.0437

Gnomad4 NFE AF: 0.0452

Gnomad4 OTH AF: 0.0662

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.22
DANN	Benign	0.76

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

LitVar

Other links and lift over

dbSNP: rs12285364; hg19: chr11-121393226;