11-121543767-G-T

Variant names:

• chr11-121543767-G-T
• rs2276346
• NM_003105.6:c.1864+41G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003105.6(SORL1):​c.1864+41G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 1,570,516 control chromosomes in the GnomAD database, including 82,361 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 0.26 (6166 hom., cov: 32)
  • Exomes 𝑓: 0.32 (76195 hom.)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.189
• Publications: 19 publications found

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]

SORL1 Gene-Disease associations (from GenCC):

• early-onset autosomal dominant Alzheimer disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.1864+41G>T		intron_variant	Intron 13 of 47	ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.1864+41G>T		intron_variant	Intron 13 of 47	1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000532451.1	n.1816+41G>T		intron_variant	Intron 13 of 14	1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39088 AN: 151946 Hom.: 6169 Cov.: 32

Gnomad AFR AF: 0.0861

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.285

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.265

GnomAD2 exomes AF: 0.289 AC: 67685 AN: 234194 AF XY: 0.299

Gnomad AFR exome AF: 0.0757

Gnomad AMR exome AF: 0.214

Gnomad ASJ exome AF: 0.385

Gnomad EAS exome AF: 0.117

Gnomad FIN exome AF: 0.398

Gnomad NFE exome AF: 0.344

Gnomad OTH exome AF: 0.333

GnomAD4 exome AF: 0.322 AC: 456518 AN: 1418452 Hom.: 76195 Cov.: 24 AF XY: 0.323 AC XY: 227528 AN XY: 704216

African (AFR) AF: 0.0720 AC: 2359 AN: 32758

American (AMR) AF: 0.218 AC: 9600 AN: 44044

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 9684 AN: 25272

East Asian (EAS) AF: 0.105 AC: 4094 AN: 39150

South Asian (SAS) AF: 0.307 AC: 25911 AN: 84504

European-Finnish (FIN) AF: 0.392 AC: 17798 AN: 45390

Middle Eastern (MID) AF: 0.339 AC: 1479 AN: 4358

European-Non Finnish (NFE) AF: 0.339 AC: 367385 AN: 1084188

Other (OTH) AF: 0.310 AC: 18208 AN: 58788

GnomAD4 genome AF: 0.257 AC: 39078 AN: 152064 Hom.: 6166 Cov.: 32 AF XY: 0.260 AC XY: 19327 AN XY: 74312

African (AFR) AF: 0.0861 AC: 3573 AN: 41518

American (AMR) AF: 0.236 AC: 3600 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 1373 AN: 3466

East Asian (EAS) AF: 0.118 AC: 610 AN: 5164

South Asian (SAS) AF: 0.285 AC: 1372 AN: 4820

European-Finnish (FIN) AF: 0.404 AC: 4262 AN: 10554

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.341 AC: 23202 AN: 67952

Other (OTH) AF: 0.262 AC: 553 AN: 2110

Alfa AF: 0.315 Hom.: 14611

Bravo AF: 0.234

Asia WGS AF: 0.194 AC: 673 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.015
DANN	Benign	0.36
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2276346; hg19: chr11-121414476;