rs11218340

Variant names:

• chr11-121560645-A-T
• rs11218340
• NM_003105.6:c.3049+988A>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.3049+988A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0711 in 152,244 control chromosomes in the GnomAD database, including 411 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 0.071 (411 hom., cov: 32)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.53
• 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=-0.64).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0774 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.3049+988A>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.3049+988A>T		intron	N/A	ENSP00000260197.6	Q92673
	SORL1	ENST00000905166.1		c.3049+988A>T		intron	N/A	ENSP00000575225.1
	SORL1	ENST00000905167.1		c.2932+988A>T		intron	N/A	ENSP00000575226.1

Frequencies

GnomAD3 genomes AF: 0.0711 AC: 10816 AN: 152126 Hom.: 409 Cov.: 32

Gnomad AFR AF: 0.0706

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0542

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.00269

Gnomad SAS AF: 0.0845

Gnomad FIN AF: 0.0995

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0763

Gnomad OTH AF: 0.0606

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

GnomAD4 genome AF: 0.0711 AC: 10818 AN: 152244 Hom.: 411 Cov.: 32 AF XY: 0.0708 AC XY: 5269 AN XY: 74430

African (AFR) AF: 0.0705 AC: 2929 AN: 41538

American (AMR) AF: 0.0540 AC: 827 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0421 AC: 146 AN: 3472

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5188

South Asian (SAS) AF: 0.0842 AC: 406 AN: 4824

European-Finnish (FIN) AF: 0.0995 AC: 1054 AN: 10592

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0764 AC: 5195 AN: 68006

Other (OTH) AF: 0.0595 AC: 126 AN: 2116

Alfa AF: 0.0744 Hom.: 57

Bravo AF: 0.0673

Asia WGS AF: 0.0340 AC: 118 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	15
DANN	Benign	0.79
PhyloP100		1.5
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: rs11218340; hg19: chr11-121431354;