11-121577545-G-A

Variant names:

• chr11-121577545-G-A
• rs3781835
• NM_003105.6:c.3580+145G>A

Variant summary

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

The NM_003105.6(SORL1):​c.3580+145G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.021 in 880,738 control chromosomes in the GnomAD database, including 363 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 (102 hom., cov: 33)
  • Exomes 𝑓: 0.019 (261 hom.)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.417
• Publications: 14 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0708 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003105.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	NM_003105.6	MANE Select	c.3580+145G>A		intron	N/A	NP_003096.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	ENST00000260197.12	TSL:1 MANE Select	c.3580+145G>A		intron	N/A	ENSP00000260197.6
	SORL1	ENST00000525532.5	TSL:2	c.412+145G>A		intron	N/A	ENSP00000434634.1
	SORL1	ENST00000534286.5	TSL:2	c.310+145G>A		intron	N/A	ENSP00000436447.1

Frequencies

GnomAD3 genomes AF: 0.0301 AC: 4582 AN: 152156 Hom.: 102 Cov.: 33

Gnomad AFR AF: 0.0573

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.0220

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.0767

Gnomad SAS AF: 0.0213

Gnomad FIN AF: 0.00792

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0174

Gnomad OTH AF: 0.0239

GnomAD4 exome AF: 0.0191 AC: 13888 AN: 728464 Hom.: 261 AF XY: 0.0190 AC XY: 6930 AN XY: 364912

African (AFR) AF: 0.0573 AC: 980 AN: 17092

American (AMR) AF: 0.0111 AC: 190 AN: 17134

Ashkenazi Jewish (ASJ) AF: 0.0116 AC: 157 AN: 13524

East Asian (EAS) AF: 0.0900 AC: 2666 AN: 29612

South Asian (SAS) AF: 0.0203 AC: 692 AN: 34080

European-Finnish (FIN) AF: 0.00815 AC: 319 AN: 39126

Middle Eastern (MID) AF: 0.0219 AC: 85 AN: 3874

European-Non Finnish (NFE) AF: 0.0151 AC: 8190 AN: 540802

Other (OTH) AF: 0.0183 AC: 609 AN: 33220

GnomAD4 genome AF: 0.0301 AC: 4584 AN: 152274 Hom.: 102 Cov.: 33 AF XY: 0.0292 AC XY: 2176 AN XY: 74458

African (AFR) AF: 0.0572 AC: 2376 AN: 41548

American (AMR) AF: 0.0220 AC: 337 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3468

East Asian (EAS) AF: 0.0770 AC: 399 AN: 5180

South Asian (SAS) AF: 0.0214 AC: 103 AN: 4824

European-Finnish (FIN) AF: 0.00792 AC: 84 AN: 10612

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0174 AC: 1184 AN: 68016

Other (OTH) AF: 0.0236 AC: 50 AN: 2116

Alfa AF: 0.0224 Hom.: 32

Bravo AF: 0.0324

Asia WGS AF: 0.0460 AC: 162 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.41
DANN	Benign	0.72
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism

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: rs3781835; hg19: chr11-121448254;