rs1010159

Variant names:

• chr11-121612692-C-T
• rs1010159
• NM_003105.6:c.5323-44C>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.5323-44C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.612 in 1,396,550 control chromosomes in the GnomAD database, including 267,884 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 0.55 (24171 hom., cov: 32)
  • Exomes 𝑓: 0.62 (243713 hom.)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.76
• Publications: 39 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.647 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.5323-44C>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.5323-44C>T		intron	N/A	ENSP00000260197.6	Q92673
	SORL1	ENST00000905166.1		c.5323-44C>T		intron	N/A	ENSP00000575225.1
	SORL1	ENST00000905167.1		c.5206-44C>T		intron	N/A	ENSP00000575226.1

Frequencies

GnomAD3 genomes AF: 0.554 AC: 84065 AN: 151874 Hom.: 24170 Cov.: 32

Gnomad AFR AF: 0.431

Gnomad AMI AF: 0.702

Gnomad AMR AF: 0.479

Gnomad ASJ AF: 0.725

Gnomad EAS AF: 0.408

Gnomad SAS AF: 0.399

Gnomad FIN AF: 0.573

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.652

Gnomad OTH AF: 0.573

GnomAD2 exomes AF: 0.549 AC: 134707 AN: 245208 AF XY: 0.550

Gnomad AFR exome AF: 0.434

Gnomad AMR exome AF: 0.408

Gnomad ASJ exome AF: 0.713

Gnomad EAS exome AF: 0.387

Gnomad FIN exome AF: 0.586

Gnomad NFE exome AF: 0.652

Gnomad OTH exome AF: 0.591

GnomAD4 exome AF: 0.619 AC: 770072 AN: 1244560 Hom.: 243713 Cov.: 16 AF XY: 0.613 AC XY: 385998 AN XY: 629986

African (AFR) AF: 0.425 AC: 12444 AN: 29258

American (AMR) AF: 0.419 AC: 18395 AN: 43884

Ashkenazi Jewish (ASJ) AF: 0.717 AC: 17684 AN: 24678

East Asian (EAS) AF: 0.463 AC: 17811 AN: 38502

South Asian (SAS) AF: 0.409 AC: 33305 AN: 81428

European-Finnish (FIN) AF: 0.585 AC: 31043 AN: 53100

Middle Eastern (MID) AF: 0.556 AC: 2971 AN: 5348

European-Non Finnish (NFE) AF: 0.660 AC: 604412 AN: 915260

Other (OTH) AF: 0.603 AC: 32007 AN: 53102

GnomAD4 genome AF: 0.553 AC: 84074 AN: 151990 Hom.: 24171 Cov.: 32 AF XY: 0.545 AC XY: 40482 AN XY: 74286

African (AFR) AF: 0.431 AC: 17860 AN: 41436

American (AMR) AF: 0.478 AC: 7304 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.725 AC: 2515 AN: 3468

East Asian (EAS) AF: 0.409 AC: 2110 AN: 5160

South Asian (SAS) AF: 0.401 AC: 1927 AN: 4810

European-Finnish (FIN) AF: 0.573 AC: 6041 AN: 10540

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.652 AC: 44306 AN: 67984

Other (OTH) AF: 0.567 AC: 1195 AN: 2108

Alfa AF: 0.591 Hom.: 7636

Bravo AF: 0.544

Asia WGS AF: 0.414 AC: 1441 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.34
DANN	Benign	0.45
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1010159; hg19: chr11-121483401;