11-121577474-C-G

Variant names:

• chr11-121577474-C-G
• rs3824966
• NM_003105.6:c.3580+74C>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.3580+74C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,390,522 control chromosomes in the GnomAD database, including 46,933 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 0.23 (5267 hom., cov: 33)
  • Exomes 𝑓: 0.25 (41666 hom.)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02
• Publications: 17 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.3580+74C>G		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+74C>G		intron_variant	Intron 25 of 47	1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000525532.5	c.412+74C>G		intron_variant	Intron 5 of 27	2		ENSP00000434634.1
SORL1	ENST00000534286.5	c.310+74C>G		intron_variant	Intron 2 of 24	2		ENSP00000436447.1
SORL1	ENST00000532694.5	c.118+74C>G		intron_variant	Intron 2 of 24	2		ENSP00000432131.1

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35670 AN: 152010 Hom.: 5244 Cov.: 33

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.566

Gnomad SAS AF: 0.468

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.247

GnomAD4 exome AF: 0.246 AC: 304922 AN: 1238394 Hom.: 41666 AF XY: 0.250 AC XY: 150276 AN XY: 601626

African (AFR) AF: 0.0928 AC: 2513 AN: 27072

American (AMR) AF: 0.488 AC: 10812 AN: 22164

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 3629 AN: 17658

East Asian (EAS) AF: 0.506 AC: 16991 AN: 33582

South Asian (SAS) AF: 0.448 AC: 22005 AN: 49108

European-Finnish (FIN) AF: 0.252 AC: 11453 AN: 45430

Middle Eastern (MID) AF: 0.263 AC: 1305 AN: 4954

European-Non Finnish (NFE) AF: 0.226 AC: 223051 AN: 988232

Other (OTH) AF: 0.262 AC: 13163 AN: 50194

GnomAD4 genome AF: 0.235 AC: 35710 AN: 152128 Hom.: 5267 Cov.: 33 AF XY: 0.245 AC XY: 18234 AN XY: 74360

African (AFR) AF: 0.105 AC: 4357 AN: 41534

American (AMR) AF: 0.394 AC: 6022 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 720 AN: 3470

East Asian (EAS) AF: 0.565 AC: 2924 AN: 5172

South Asian (SAS) AF: 0.467 AC: 2247 AN: 4816

European-Finnish (FIN) AF: 0.260 AC: 2751 AN: 10568

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.234 AC: 15917 AN: 67966

Other (OTH) AF: 0.256 AC: 540 AN: 2110

Alfa AF: 0.122 Hom.: 223

Bravo AF: 0.236

Asia WGS AF: 0.504 AC: 1752 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.53
DANN	Benign	0.55
PhyloP100		-1.0
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: rs3824966; hg19: chr11-121448183; COSMIC: COSV52749553;