chr11-121478402-A-G

Variant names:

• chr11-121478402-A-G
• rs11218304
• NM_003105.6:c.528+159A>G

Variant summary

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

The NM_003105.6(SORL1):​c.528+159A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 152,064 control chromosomes in the GnomAD database, including 8,045 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 0.30 (8045 hom., cov: 32)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.679
• Publications: 10 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

LOC105369535 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.391 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	NM_003105.6	MANE Select	c.528+159A>G		intron	N/A	NP_003096.2
	LOC105369535	NR_169501.2		n.471T>C		non_coding_transcript_exon	Exon 3 of 5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	ENST00000260197.12	TSL:1 MANE Select	c.528+159A>G		intron	N/A	ENSP00000260197.6
	SORL1	ENST00000532451.1	TSL:1	n.480+159A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.304 AC: 46260 AN: 151946 Hom.: 8049 Cov.: 32

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.444

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.457

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.308

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

GnomAD4 genome AF: 0.304 AC: 46239 AN: 152064 Hom.: 8045 Cov.: 32 AF XY: 0.302 AC XY: 22446 AN XY: 74316

African (AFR) AF: 0.152 AC: 6318 AN: 41470

American (AMR) AF: 0.276 AC: 4215 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 1584 AN: 3468

East Asian (EAS) AF: 0.125 AC: 648 AN: 5176

South Asian (SAS) AF: 0.311 AC: 1498 AN: 4824

European-Finnish (FIN) AF: 0.376 AC: 3976 AN: 10568

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.395 AC: 26820 AN: 67968

Other (OTH) AF: 0.305 AC: 643 AN: 2108

Alfa AF: 0.339 Hom.: 1175

Bravo AF: 0.288

Asia WGS AF: 0.202 AC: 704 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.77
DANN	Benign	0.51
PhyloP100		-0.68
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: rs11218304; hg19: chr11-121349111;