chr11-121575231-A-G

Variant names:

• chr11-121575231-A-G
• rs3781834
• NM_003105.6:c.3460+868A>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.3460+868A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 152,314 control chromosomes in the GnomAD database, including 167 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 0.028 (167 hom., cov: 32)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.228
• Publications: 13 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.3460+868A>G		intron_variant	Intron 24 of 47	ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.3460+868A>G		intron_variant	Intron 24 of 47	1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000525532.5	c.292+868A>G		intron_variant	Intron 4 of 27	2		ENSP00000434634.1

Frequencies

GnomAD3 genomes AF: 0.0276 AC: 4199 AN: 152196 Hom.: 168 Cov.: 32

Gnomad AFR AF: 0.00608

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0450

Gnomad ASJ AF: 0.0525

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.0511

Gnomad FIN AF: 0.0168

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0214

Gnomad OTH AF: 0.0283

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

GnomAD4 genome AF: 0.0275 AC: 4190 AN: 152314 Hom.: 167 Cov.: 32 AF XY: 0.0293 AC XY: 2186 AN XY: 74498

African (AFR) AF: 0.00606 AC: 252 AN: 41592

American (AMR) AF: 0.0450 AC: 689 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0525 AC: 182 AN: 3468

East Asian (EAS) AF: 0.215 AC: 1115 AN: 5180

South Asian (SAS) AF: 0.0501 AC: 242 AN: 4828

European-Finnish (FIN) AF: 0.0168 AC: 178 AN: 10624

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0214 AC: 1455 AN: 68004

Other (OTH) AF: 0.0280 AC: 59 AN: 2110

Alfa AF: 0.0290 Hom.: 253

Bravo AF: 0.0305

Asia WGS AF: 0.113 AC: 393 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.2
DANN	Benign	0.64
PhyloP100		-0.23
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: rs3781834; hg19: chr11-121445940;