rs11600231

Variant names:

• chr11-121535999-T-C
• rs11600231
• NM_003105.6:c.1685+3447T>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.1685+3447T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0786 in 152,242 control chromosomes in the GnomAD database, including 503 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 0.079 (503 hom., cov: 31)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.289
• Publications: 4 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=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0896 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORL1	NM_003105.6	c.1685+3447T>C		intron_variant	Intron 12 of 47	ENST00000260197.12	NP_003096.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORL1	ENST00000260197.12	c.1685+3447T>C		intron_variant	Intron 12 of 47	1	NM_003105.6	ENSP00000260197.6
SORL1	ENST00000532451.1	n.1637+3447T>C		intron_variant	Intron 12 of 14	1

Frequencies

GnomAD3 genomes AF: 0.0786 AC: 11954 AN: 152124 Hom.: 503 Cov.: 31

Gnomad AFR AF: 0.0797

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0707

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0597

Gnomad FIN AF: 0.0344

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0915

Gnomad OTH AF: 0.0876

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

GnomAD4 genome AF: 0.0786 AC: 11959 AN: 152242 Hom.: 503 Cov.: 31 AF XY: 0.0745 AC XY: 5549 AN XY: 74446

African (AFR) AF: 0.0797 AC: 3309 AN: 41534

American (AMR) AF: 0.0706 AC: 1080 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 399 AN: 3466

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5186

South Asian (SAS) AF: 0.0595 AC: 287 AN: 4822

European-Finnish (FIN) AF: 0.0344 AC: 365 AN: 10612

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.0915 AC: 6222 AN: 68004

Other (OTH) AF: 0.0866 AC: 183 AN: 2112

Alfa AF: 0.0846 Hom.: 219

Bravo AF: 0.0834

Asia WGS AF: 0.0350 AC: 120 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.6
DANN	Benign	0.65
PhyloP100		0.29
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: rs11600231; hg19: chr11-121406708;