rs2298814

chr11-121554173-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.2439+64G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,463,470 control chromosomes in the GnomAD database, including 478 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 0.030 (97 hom., cov: 33)
  • Exomes 𝑓: 0.019 (381 hom.)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.489

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 = 0.0749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORL1	NM_003105.6	c.2439+64G>A		intron_variant		ENST00000260197.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORL1	ENST00000260197.12	c.2439+64G>A		intron_variant		1	NM_003105.6	P1

Frequencies

GnomAD3 genomes AF: 0.0300 AC: 4562 AN: 152198 Hom.: 97 Cov.: 33

Gnomad AFR AF: 0.0565

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0217

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.0809

Gnomad SAS AF: 0.0217

Gnomad FIN AF: 0.00791

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0174

Gnomad OTH AF: 0.0206

GnomAD4 exome AF: 0.0195 AC: 25513 AN: 1311154 Hom.: 381 AF XY: 0.0194 AC XY: 12610 AN XY: 650122

Gnomad4 AFR exome AF: 0.0590

Gnomad4 AMR exome AF: 0.0109

Gnomad4 ASJ exome AF: 0.0116

Gnomad4 EAS exome AF: 0.0879

Gnomad4 SAS exome AF: 0.0212

Gnomad4 FIN exome AF: 0.00818

Gnomad4 NFE exome AF: 0.0166

Gnomad4 OTH exome AF: 0.0200

GnomAD4 genome AF: 0.0300 AC: 4566 AN: 152316 Hom.: 97 Cov.: 33 AF XY: 0.0292 AC XY: 2178 AN XY: 74464

Gnomad4 AFR AF: 0.0564

Gnomad4 AMR AF: 0.0216

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.0813

Gnomad4 SAS AF: 0.0217

Gnomad4 FIN AF: 0.00791

Gnomad4 NFE AF: 0.0174

Gnomad4 OTH AF: 0.0203

Alfa AF: 0.0283 Hom.: 15

Bravo AF: 0.0324

Asia WGS AF: 0.0480 AC: 167 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	1.0
Dann	Benign	0.74

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: rs2298814; hg19: chr11-121424882; COSMIC: COSV52754612; COSMIC: COSV52754612;