rs689021

Variant names:

• chr11-121500411-G-A
• rs689021
• NM_003105.6:c.939+3362G>A

Variant summary

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

The NM_003105.6(SORL1):​c.939+3362G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.401 in 152,096 control chromosomes in the GnomAD database, including 12,689 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 0.40 (12689 hom., cov: 33)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0680
• Publications: 32 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.939+3362G>A		intron_variant	Intron 6 of 47	ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.939+3362G>A		intron_variant	Intron 6 of 47	1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000532451.1	n.891+3362G>A		intron_variant	Intron 6 of 14	1

Frequencies

GnomAD3 genomes AF: 0.401 AC: 61007 AN: 151978 Hom.: 12671 Cov.: 33

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.549

Gnomad SAS AF: 0.448

Gnomad FIN AF: 0.476

Gnomad MID AF: 0.331

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.403

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

GnomAD4 genome AF: 0.401 AC: 61054 AN: 152096 Hom.: 12689 Cov.: 33 AF XY: 0.401 AC XY: 29804 AN XY: 74364

African (AFR) AF: 0.309 AC: 12837 AN: 41494

American (AMR) AF: 0.360 AC: 5496 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 1172 AN: 3466

East Asian (EAS) AF: 0.549 AC: 2840 AN: 5174

South Asian (SAS) AF: 0.447 AC: 2153 AN: 4816

European-Finnish (FIN) AF: 0.476 AC: 5036 AN: 10574

Middle Eastern (MID) AF: 0.339 AC: 99 AN: 292

European-Non Finnish (NFE) AF: 0.446 AC: 30304 AN: 67976

Other (OTH) AF: 0.409 AC: 863 AN: 2110

Alfa AF: 0.429 Hom.: 7393

Bravo AF: 0.391

Asia WGS AF: 0.502 AC: 1745 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.4
DANN	Benign	0.58
PhyloP100		0.068
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: rs689021; hg19: chr11-121371120;