rs661057

Variant names:

• chr11-121458245-T-C
• rs661057
• NM_003105.6:c.285+5629T>C

Variant summary

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

The NM_003105.6(SORL1):​c.285+5629T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 152,094 control chromosomes in the GnomAD database, including 13,147 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 0.41 (13147 hom., cov: 33)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0810
• Publications: 20 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.529 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.285+5629T>C		intron_variant	Intron 1 of 47	ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.285+5629T>C		intron_variant	Intron 1 of 47	1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000532451.1	n.237+5629T>C		intron_variant	Intron 1 of 14	1

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61730 AN: 151976 Hom.: 13128 Cov.: 33

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.396

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.547

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.502

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.449

Gnomad OTH AF: 0.396

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.406 AC: 61785 AN: 152094 Hom.: 13147 Cov.: 33 AF XY: 0.406 AC XY: 30215 AN XY: 74342

African (AFR) AF: 0.301 AC: 12473 AN: 41498

American (AMR) AF: 0.397 AC: 6058 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1002 AN: 3472

East Asian (EAS) AF: 0.546 AC: 2822 AN: 5166

South Asian (SAS) AF: 0.487 AC: 2351 AN: 4828

European-Finnish (FIN) AF: 0.502 AC: 5308 AN: 10572

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.449 AC: 30496 AN: 67970

Other (OTH) AF: 0.402 AC: 849 AN: 2110

Alfa AF: 0.426 Hom.: 25627

Bravo AF: 0.392

Asia WGS AF: 0.512 AC: 1778 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	9.1
DANN	Benign	0.48
PhyloP100		0.081
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: rs661057; hg19: chr11-121328954;