rs1784933

chr11-121618707-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.5605-67G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.921 in 1,596,528 control chromosomes in the GnomAD database, including 683,552 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 0.84 (55544 hom., cov: 31)
  • Exomes 𝑓: 0.93 (628008 hom.)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.365

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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORL1	NM_003105.6	c.5605-67G>A		intron_variant		ENST00000260197.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORL1	ENST00000260197.12	c.5605-67G>A		intron_variant		1	NM_003105.6	P1

Frequencies

GnomAD3 genomes AF: 0.842 AC: 127973 AN: 151966 Hom.: 55523 Cov.: 31

Gnomad AFR AF: 0.622

Gnomad AMI AF: 0.908

Gnomad AMR AF: 0.851

Gnomad ASJ AF: 0.942

Gnomad EAS AF: 0.690

Gnomad SAS AF: 0.916

Gnomad FIN AF: 0.985

Gnomad MID AF: 0.934

Gnomad NFE AF: 0.950

Gnomad OTH AF: 0.881

GnomAD4 exome AF: 0.929 AC: 1341945 AN: 1444444 Hom.: 628008 AF XY: 0.931 AC XY: 668956 AN XY: 718736

Gnomad4 AFR exome AF: 0.604

Gnomad4 AMR exome AF: 0.791

Gnomad4 ASJ exome AF: 0.943

Gnomad4 EAS exome AF: 0.635

Gnomad4 SAS exome AF: 0.925

Gnomad4 FIN exome AF: 0.982

Gnomad4 NFE exome AF: 0.953

Gnomad4 OTH exome AF: 0.912

GnomAD4 genome AF: 0.842 AC: 128038 AN: 152084 Hom.: 55544 Cov.: 31 AF XY: 0.845 AC XY: 62838 AN XY: 74354

Gnomad4 AFR AF: 0.622

Gnomad4 AMR AF: 0.851

Gnomad4 ASJ AF: 0.942

Gnomad4 EAS AF: 0.690

Gnomad4 SAS AF: 0.917

Gnomad4 FIN AF: 0.985

Gnomad4 NFE AF: 0.950

Gnomad4 OTH AF: 0.882

Alfa AF: 0.921 Hom.: 73957

Bravo AF: 0.817

Asia WGS AF: 0.812 AC: 2826 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	3.3
Dann	Benign	0.51

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: rs1784933; hg19: chr11-121489416; COSMIC: COSV52755379;