11-121452768-G-C

Variant names:

• chr11-121452768-G-C
• rs578506
• NM_003105.6:c.285+152G>C

Variant summary

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

The NM_003105.6(SORL1):​c.285+152G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.468 in 596,972 control chromosomes in the GnomAD database, including 70,991 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 0.39 (14096 hom., cov: 32)
  • Exomes 𝑓: 0.50 (56895 hom.)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.376
• Publications: 9 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-AS1 (HGNC:55594): (SORL1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.65 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003105.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	NM_003105.6	MANE Select	c.285+152G>C		intron	N/A	NP_003096.2
	SORL1-AS1	NR_183636.1	MANE Select	n.200C>G		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	ENST00000260197.12	TSL:1 MANE Select	c.285+152G>C		intron	N/A	ENSP00000260197.6
	SORL1-AS1	ENST00000529160.2	TSL:2 MANE Select	n.200C>G		non_coding_transcript_exon	Exon 1 of 3
	SORL1	ENST00000532451.1	TSL:1	n.237+152G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.386 AC: 58600 AN: 151774 Hom.: 14091 Cov.: 32

Gnomad AFR AF: 0.0912

Gnomad AMI AF: 0.510

Gnomad AMR AF: 0.509

Gnomad ASJ AF: 0.511

Gnomad EAS AF: 0.669

Gnomad SAS AF: 0.607

Gnomad FIN AF: 0.470

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.383

GnomAD4 exome AF: 0.496 AC: 220549 AN: 445082 Hom.: 56895 Cov.: 6 AF XY: 0.500 AC XY: 114776 AN XY: 229456

African (AFR) AF: 0.0877 AC: 837 AN: 9548

American (AMR) AF: 0.528 AC: 4424 AN: 8376

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 6138 AN: 12052

East Asian (EAS) AF: 0.749 AC: 17642 AN: 23542

South Asian (SAS) AF: 0.599 AC: 19227 AN: 32108

European-Finnish (FIN) AF: 0.485 AC: 13795 AN: 28464

Middle Eastern (MID) AF: 0.433 AC: 866 AN: 1998

European-Non Finnish (NFE) AF: 0.480 AC: 145929 AN: 304316

Other (OTH) AF: 0.474 AC: 11691 AN: 24678

GnomAD4 genome AF: 0.386 AC: 58608 AN: 151890 Hom.: 14096 Cov.: 32 AF XY: 0.394 AC XY: 29227 AN XY: 74216

African (AFR) AF: 0.0910 AC: 3760 AN: 41336

American (AMR) AF: 0.509 AC: 7778 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 1774 AN: 3470

East Asian (EAS) AF: 0.669 AC: 3451 AN: 5162

South Asian (SAS) AF: 0.607 AC: 2929 AN: 4822

European-Finnish (FIN) AF: 0.470 AC: 4961 AN: 10546

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.479 AC: 32535 AN: 67958

Other (OTH) AF: 0.389 AC: 818 AN: 2104

Alfa AF: 0.420 Hom.: 1887

Bravo AF: 0.370

Asia WGS AF: 0.624 AC: 2165 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Benign	0.80
PhyloP100		0.38
PromoterAI		-0.048	Neutral
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: rs578506; hg19: chr11-121323477; COSMIC: COSV106055016;