11-121568956-T-C

Variant names:

• chr11-121568956-T-C
• rs1784919
• NM_003105.6:c.3224-1201T>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.3224-1201T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.948 in 152,272 control chromosomes in the GnomAD database, including 68,617 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 0.95 (68617 hom., cov: 32)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.71
• Publications: 3 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=-1.01).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.975 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.3224-1201T>C		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.3224-1201T>C		intron	N/A	ENSP00000260197.6	Q92673
	SORL1	ENST00000905166.1		c.3224-1201T>C		intron	N/A	ENSP00000575225.1
	SORL1	ENST00000905167.1		c.3107-1201T>C		intron	N/A	ENSP00000575226.1

Frequencies

GnomAD3 genomes AF: 0.948 AC: 144208 AN: 152154 Hom.: 68587 Cov.: 32

Gnomad AFR AF: 0.866

Gnomad AMI AF: 0.979

Gnomad AMR AF: 0.971

Gnomad ASJ AF: 0.988

Gnomad EAS AF: 0.929

Gnomad SAS AF: 0.979

Gnomad FIN AF: 0.992

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.981

Gnomad OTH AF: 0.962

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

GnomAD4 genome AF: 0.948 AC: 144295 AN: 152272 Hom.: 68617 Cov.: 32 AF XY: 0.950 AC XY: 70734 AN XY: 74438

African (AFR) AF: 0.866 AC: 35952 AN: 41514

American (AMR) AF: 0.971 AC: 14864 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.988 AC: 3432 AN: 3472

East Asian (EAS) AF: 0.929 AC: 4816 AN: 5184

South Asian (SAS) AF: 0.979 AC: 4721 AN: 4824

European-Finnish (FIN) AF: 0.992 AC: 10534 AN: 10620

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 0.981 AC: 66762 AN: 68036

Other (OTH) AF: 0.963 AC: 2033 AN: 2112

Alfa AF: 0.959 Hom.: 3664

Bravo AF: 0.942

Asia WGS AF: 0.951 AC: 3307 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.12
DANN	Benign	0.18
PhyloP100		-2.7
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: rs1784919; hg19: chr11-121439665;