NM_003105.6:c.690+363T>C

Variant names:

• chr11-121488556-T-C
• rs676759
• NM_003105.6:c.690+363T>C

Variant summary

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

The NM_003105.6(SORL1):​c.690+363T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 151,978 control chromosomes in the GnomAD database, including 10,940 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 (10940 hom., cov: 32)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.490
• Publications: 10 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.690+363T>C		intron_variant	Intron 4 of 47	ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.690+363T>C		intron_variant	Intron 4 of 47	1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000532451.1	n.642+363T>C		intron_variant	Intron 4 of 14	1

Frequencies

GnomAD3 genomes AF: 0.373 AC: 56627 AN: 151860 Hom.: 10918 Cov.: 32

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.275

Gnomad EAS AF: 0.554

Gnomad SAS AF: 0.450

Gnomad FIN AF: 0.460

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.357

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.373 AC: 56687 AN: 151978 Hom.: 10940 Cov.: 32 AF XY: 0.375 AC XY: 27838 AN XY: 74288

African (AFR) AF: 0.305 AC: 12646 AN: 41440

American (AMR) AF: 0.327 AC: 4998 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 954 AN: 3468

East Asian (EAS) AF: 0.554 AC: 2867 AN: 5176

South Asian (SAS) AF: 0.449 AC: 2164 AN: 4820

European-Finnish (FIN) AF: 0.460 AC: 4855 AN: 10562

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.399 AC: 27137 AN: 67936

Other (OTH) AF: 0.364 AC: 766 AN: 2102

Alfa AF: 0.387 Hom.: 48133

Bravo AF: 0.360

Asia WGS AF: 0.505 AC: 1756 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	7.5
DANN	Benign	0.34
PhyloP100		0.49
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: rs676759; hg19: chr11-121359265;