11-121608249-C-T

Position:

• chr11-121608249-C-T

Variant summary

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

The ENST00000260197.12(SORL1):​c.5239+73C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,222,666 control chromosomes in the GnomAD database, including 64,750 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 0.28 (7055 hom., cov: 32)
  • Exomes 𝑓: 0.31 (57695 hom.)
• Consequence: SORL1 ENST00000260197.12 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.65

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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SORL1	NM_003105.6	c.5239+73C>T		intron_variant		ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.5239+73C>T		intron_variant		1	NM_003105.6	ENSP00000260197	P1

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41870 AN: 151898 Hom.: 7038 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.414

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.585

Gnomad SAS AF: 0.502

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.292

Gnomad OTH AF: 0.278

GnomAD4 exome AF: 0.314 AC: 336584 AN: 1070650 Hom.: 57695 Cov.: 14 AF XY: 0.321 AC XY: 175087 AN XY: 546038

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.503

Gnomad4 ASJ exome AF: 0.207

Gnomad4 EAS exome AF: 0.531

Gnomad4 SAS exome AF: 0.491

Gnomad4 FIN exome AF: 0.378

Gnomad4 NFE exome AF: 0.285

Gnomad4 OTH exome AF: 0.308

GnomAD4 genome AF: 0.276 AC: 41909 AN: 152016 Hom.: 7055 Cov.: 32 AF XY: 0.288 AC XY: 21389 AN XY: 74288

Gnomad4 AFR AF: 0.112

Gnomad4 AMR AF: 0.415

Gnomad4 ASJ AF: 0.207

Gnomad4 EAS AF: 0.584

Gnomad4 SAS AF: 0.501

Gnomad4 FIN AF: 0.389

Gnomad4 NFE AF: 0.292

Gnomad4 OTH AF: 0.286

Alfa AF: 0.289 Hom.: 1490

Bravo AF: 0.268

Asia WGS AF: 0.514 AC: 1787 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.23
DANN	Benign	0.62

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: rs2282649; hg19: chr11-121478958; COSMIC: COSV52762440; COSMIC: COSV52762440;