rs560573

Positions:

• chr11-121490175-T-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+65T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 1,133,190 control chromosomes in the GnomAD database, including 88,946 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 0.37 (10770 hom., cov: 32)
  • Exomes 𝑓: 0.40 (78176 hom.)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.978

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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SORL1	NM_003105.6	c.758+65T>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+65T>A		intron_variant		1	NM_003105.6	ENSP00000260197	P1
SORL1	ENST00000532451.1	n.710+65T>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56176 AN: 151880 Hom.: 10749 Cov.: 32

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.273

Gnomad EAS AF: 0.550

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.459

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.354

GnomAD4 exome AF: 0.397 AC: 389103 AN: 981192 Hom.: 78176 AF XY: 0.398 AC XY: 202250 AN XY: 507652

Gnomad4 AFR exome AF: 0.302

Gnomad4 AMR exome AF: 0.365

Gnomad4 ASJ exome AF: 0.282

Gnomad4 EAS exome AF: 0.522

Gnomad4 SAS exome AF: 0.437

Gnomad4 FIN exome AF: 0.443

Gnomad4 NFE exome AF: 0.392

Gnomad4 OTH exome AF: 0.383

GnomAD4 genome AF: 0.370 AC: 56228 AN: 151998 Hom.: 10770 Cov.: 32 AF XY: 0.372 AC XY: 27608 AN XY: 74290

Gnomad4 AFR AF: 0.302

Gnomad4 AMR AF: 0.325

Gnomad4 ASJ AF: 0.273

Gnomad4 EAS AF: 0.549

Gnomad4 SAS AF: 0.444

Gnomad4 FIN AF: 0.459

Gnomad4 NFE AF: 0.396

Gnomad4 OTH AF: 0.361

Alfa AF: 0.377 Hom.: 1355

Bravo AF: 0.357

Asia WGS AF: 0.498 AC: 1733 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.035
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: rs560573; hg19: chr11-121360884; COSMIC: COSV52751338;