11-121577474-C-G

Position:

• chr11-121577474-C-G

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
SORL1	NM_003105.6	c.3580+74C>G		intron_variant		ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.3580+74C>G		intron_variant		1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000525532.5	c.412+74C>G		intron_variant		2		ENSP00000434634.1
SORL1	ENST00000534286.5	c.310+74C>G		intron_variant		2		ENSP00000436447.1
SORL1	ENST00000532694.5	c.118+74C>G		intron_variant		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

Gnomad4 AFR exome AF: 0.0928

Gnomad4 AMR exome AF: 0.488

Gnomad4 ASJ exome AF: 0.206

Gnomad4 EAS exome AF: 0.506

Gnomad4 SAS exome AF: 0.448

Gnomad4 FIN exome AF: 0.252

Gnomad4 NFE exome AF: 0.226

Gnomad4 OTH exome AF: 0.262

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

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.394

Gnomad4 ASJ AF: 0.207

Gnomad4 EAS AF: 0.565

Gnomad4 SAS AF: 0.467

Gnomad4 FIN AF: 0.260

Gnomad4 NFE AF: 0.234

Gnomad4 OTH AF: 0.256

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs3824966; hg19: chr11-121448183; COSMIC: COSV52749553;