rs985421

Positions:

• chr11-121491607-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.758+1497G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0325 in 152,222 control chromosomes in the GnomAD database, including 338 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 0.033 (338 hom., cov: 32)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.56

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=-0.96).
• 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.758+1497G>A		intron_variant		ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.758+1497G>A		intron_variant		1	NM_003105.6	ENSP00000260197	P1
SORL1	ENST00000532451.1	n.710+1497G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0325 AC: 4950 AN: 152102 Hom.: 339 Cov.: 32

Gnomad AFR AF: 0.00546

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.0284

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0145

Gnomad OTH AF: 0.0335

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

GnomAD4 genome AF: 0.0325 AC: 4952 AN: 152222 Hom.: 338 Cov.: 32 AF XY: 0.0363 AC XY: 2702 AN XY: 74424

Gnomad4 AFR AF: 0.00542

Gnomad4 AMR AF: 0.154

Gnomad4 ASJ AF: 0.0182

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.0280

Gnomad4 FIN AF: 0.0103

Gnomad4 NFE AF: 0.0145

Gnomad4 OTH AF: 0.0336

Alfa AF: 0.0307 Hom.: 69

Bravo AF: 0.0412

Asia WGS AF: 0.0960 AC: 334 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.0030
DANN	Benign	0.42

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: rs985421; hg19: chr11-121362316;