rs11600875

Variant names:

• chr11-121486259-C-T
• rs11600875
• NM_003105.6:c.529-1773C>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.529-1773C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 152,138 control chromosomes in the GnomAD database, including 1,014 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 0.10 (1014 hom., cov: 31)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.654
• Publications: 8 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 (AFR) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.529-1773C>T		intron_variant	Intron 3 of 47	ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.529-1773C>T		intron_variant	Intron 3 of 47	1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000532451.1	n.481-1773C>T		intron_variant	Intron 3 of 14	1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15761 AN: 152020 Hom.: 1012 Cov.: 31

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.0794

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.00443

Gnomad SAS AF: 0.0656

Gnomad FIN AF: 0.0228

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0868

Gnomad OTH AF: 0.0984

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

GnomAD4 genome AF: 0.104 AC: 15771 AN: 152138 Hom.: 1014 Cov.: 31 AF XY: 0.100 AC XY: 7473 AN XY: 74388

African (AFR) AF: 0.177 AC: 7341 AN: 41458

American (AMR) AF: 0.0792 AC: 1212 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 373 AN: 3472

East Asian (EAS) AF: 0.00444 AC: 23 AN: 5180

South Asian (SAS) AF: 0.0664 AC: 320 AN: 4816

European-Finnish (FIN) AF: 0.0228 AC: 242 AN: 10604

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0868 AC: 5903 AN: 67990

Other (OTH) AF: 0.0974 AC: 206 AN: 2116

Alfa AF: 0.0926 Hom.: 391

Bravo AF: 0.112

Asia WGS AF: 0.0400 AC: 138 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	0.27
DANN	Benign	0.73
PhyloP100		-0.65
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: rs11600875; hg19: chr11-121356968;