rs596437

Variant names:

• chr11-121499314-A-G
• rs596437
• NM_003105.6:c.939+2265A>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.939+2265A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 151,966 control chromosomes in the GnomAD database, including 12,698 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 0.40 (12698 hom., cov: 31)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.498
• Publications: 4 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.536 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.939+2265A>G		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.939+2265A>G		intron	N/A	ENSP00000260197.6	Q92673
	SORL1	ENST00000532451.1	TSL:1	n.891+2265A>G		intron	N/A
	SORL1	ENST00000905166.1		c.939+2265A>G		intron	N/A	ENSP00000575225.1

Frequencies

GnomAD3 genomes AF: 0.402 AC: 61014 AN: 151848 Hom.: 12680 Cov.: 31

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.554

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.477

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.404

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

GnomAD4 genome AF: 0.402 AC: 61061 AN: 151966 Hom.: 12698 Cov.: 31 AF XY: 0.401 AC XY: 29810 AN XY: 74268

African (AFR) AF: 0.310 AC: 12830 AN: 41438

American (AMR) AF: 0.359 AC: 5491 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 1173 AN: 3472

East Asian (EAS) AF: 0.553 AC: 2853 AN: 5156

South Asian (SAS) AF: 0.452 AC: 2169 AN: 4798

European-Finnish (FIN) AF: 0.477 AC: 5033 AN: 10560

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.446 AC: 30297 AN: 67950

Other (OTH) AF: 0.410 AC: 864 AN: 2108

Alfa AF: 0.411 Hom.: 2152

Bravo AF: 0.391

Asia WGS AF: 0.505 AC: 1755 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.97
DANN	Benign	0.81
PhyloP100		-0.50
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: rs596437; hg19: chr11-121370023;