rs3781836

Variant names:

• chr11-121577629-G-A
• rs3781836
• NM_003105.6:c.3580+229G>A

Variant summary

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

The NM_003105.6(SORL1):​c.3580+229G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 152,170 control chromosomes in the GnomAD database, including 3,072 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 0.18 (3072 hom., cov: 32)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.576
• Publications: 5 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.3580+229G>A		intron_variant	Intron 25 of 47	ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.3580+229G>A		intron_variant	Intron 25 of 47	1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000525532.5	c.412+229G>A		intron_variant	Intron 5 of 27	2		ENSP00000434634.1
SORL1	ENST00000534286.5	c.310+229G>A		intron_variant	Intron 2 of 24	2		ENSP00000436447.1
SORL1	ENST00000532694.5	c.118+229G>A		intron_variant	Intron 2 of 24	2		ENSP00000432131.1

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27349 AN: 152052 Hom.: 3067 Cov.: 32

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.169

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

GnomAD4 genome AF: 0.180 AC: 27361 AN: 152170 Hom.: 3072 Cov.: 32 AF XY: 0.180 AC XY: 13360 AN XY: 74392

African (AFR) AF: 0.313 AC: 12981 AN: 41472

American (AMR) AF: 0.149 AC: 2277 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 359 AN: 3466

East Asian (EAS) AF: 0.212 AC: 1102 AN: 5188

South Asian (SAS) AF: 0.118 AC: 571 AN: 4830

European-Finnish (FIN) AF: 0.133 AC: 1403 AN: 10586

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.120 AC: 8168 AN: 68014

Other (OTH) AF: 0.167 AC: 352 AN: 2108

Alfa AF: 0.138 Hom.: 6408

Bravo AF: 0.189

Asia WGS AF: 0.158 AC: 552 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.2
DANN	Benign	0.73
PhyloP100		-0.58
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: rs3781836; hg19: chr11-121448338; COSMIC: COSV52752787;