rs4598682

Positions:

• chr11-121505242-A-G

Variant summary

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

The NM_003105.6(SORL1):​c.940-7761A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0422 in 152,044 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 0.042 (363 hom., cov: 32)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.495

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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SORL1	NM_003105.6	c.940-7761A>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.940-7761A>G		intron_variant		1	NM_003105.6	ENSP00000260197	P1
SORL1	ENST00000532451.1	n.892-7761A>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0421 AC: 6401 AN: 151924 Hom.: 364 Cov.: 32

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.0439

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.0379

Gnomad FIN AF: 0.0497

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0188

Gnomad OTH AF: 0.0435

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0422 AC: 6412 AN: 152044 Hom.: 363 Cov.: 32 AF XY: 0.0481 AC XY: 3577 AN XY: 74354

Gnomad4 AFR AF: 0.0174

Gnomad4 AMR AF: 0.156

Gnomad4 ASJ AF: 0.0439

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.0375

Gnomad4 FIN AF: 0.0497

Gnomad4 NFE AF: 0.0188

Gnomad4 OTH AF: 0.0436

Alfa AF: 0.0285 Hom.: 27

Bravo AF: 0.0480

Asia WGS AF: 0.107 AC: 368 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.5
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: rs4598682; hg19: chr11-121375951;