rs3781835

chr11-121577545-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003105.6(SORL1):c.3580+145G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.021 in 880,738 control chromosomes in the GnomAD database, including 363 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 0.030 (102 hom., cov: 33)
  • Exomes 𝑓: 0.019 (261 hom.)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.417

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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0708 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORL1	NM_003105.6	c.3580+145G>A		intron_variant		ENST00000260197.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORL1	ENST00000260197.12	c.3580+145G>A		intron_variant		1	NM_003105.6	P1
SORL1	ENST00000525532.5	c.412+145G>A		intron_variant		2
SORL1	ENST00000532694.5	c.118+145G>A		intron_variant		2
SORL1	ENST00000534286.5	c.310+145G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0301 AC: 4582 AN: 152156 Hom.: 102 Cov.: 33

Gnomad AFR AF: 0.0573

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.0220

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.0767

Gnomad SAS AF: 0.0213

Gnomad FIN AF: 0.00792

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0174

Gnomad OTH AF: 0.0239

GnomAD4 exome AF: 0.0191 AC: 13888 AN: 728464 Hom.: 261 AF XY: 0.0190 AC XY: 6930 AN XY: 364912

Gnomad4 AFR exome AF: 0.0573

Gnomad4 AMR exome AF: 0.0111

Gnomad4 ASJ exome AF: 0.0116

Gnomad4 EAS exome AF: 0.0900

Gnomad4 SAS exome AF: 0.0203

Gnomad4 FIN exome AF: 0.00815

Gnomad4 NFE exome AF: 0.0151

Gnomad4 OTH exome AF: 0.0183

GnomAD4 genome AF: 0.0301 AC: 4584 AN: 152274 Hom.: 102 Cov.: 33 AF XY: 0.0292 AC XY: 2176 AN XY: 74458

Gnomad4 AFR AF: 0.0572

Gnomad4 AMR AF: 0.0220

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.0770

Gnomad4 SAS AF: 0.0214

Gnomad4 FIN AF: 0.00792

Gnomad4 NFE AF: 0.0174

Gnomad4 OTH AF: 0.0236

Alfa AF: 0.0224 Hom.: 27

Bravo AF: 0.0324

Asia WGS AF: 0.0460 AC: 162 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.41
Dann	Benign	0.72

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: rs3781835; hg19: chr11-121448254;