rs7946599

Positions:

• chr11-121552931-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.2267-1006G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0322 in 152,266 control chromosomes in the GnomAD database, including 118 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 0.032 (118 hom., cov: 33)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0990

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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0834 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORL1	NM_003105.6	c.2267-1006G>A		intron_variant		ENST00000260197.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORL1	ENST00000260197.12	c.2267-1006G>A		intron_variant		1	NM_003105.6	P1

Frequencies

GnomAD3 genomes AF: 0.0322 AC: 4892 AN: 152148 Hom.: 118 Cov.: 33

Gnomad AFR AF: 0.0633

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0223

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.0898

Gnomad SAS AF: 0.0213

Gnomad FIN AF: 0.00773

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0174

Gnomad OTH AF: 0.0220

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

GnomAD4 genome AF: 0.0322 AC: 4898 AN: 152266 Hom.: 118 Cov.: 33 AF XY: 0.0313 AC XY: 2331 AN XY: 74472

Gnomad4 AFR AF: 0.0632

Gnomad4 AMR AF: 0.0222

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.0902

Gnomad4 SAS AF: 0.0213

Gnomad4 FIN AF: 0.00773

Gnomad4 NFE AF: 0.0174

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0305 Hom.: 13

Bravo AF: 0.0350

Asia WGS AF: 0.0500 AC: 174 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.5
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs7946599; hg19: chr11-121423640;