11-121577545-G-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003105.6(SORL1):​c.3580+145G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 728,684 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SORL1 NM_003105.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.417
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

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>T		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>T		intron	N/A	ENSP00000260197.6
	SORL1	ENST00000525532.5	TSL:2	c.412+145G>T		intron	N/A	ENSP00000434634.1
	SORL1	ENST00000534286.5	TSL:2	c.310+145G>T		intron	N/A	ENSP00000436447.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 1 AN: 728684 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 365012

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 17104

American (AMR) AF: 0.00 AC: 0 AN: 17136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13524

East Asian (EAS) AF: 0.00 AC: 0 AN: 29632

South Asian (SAS) AF: 0.00 AC: 0 AN: 34094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3874

European-Non Finnish (NFE) AF: 0.00000185 AC: 1 AN: 540962

Other (OTH) AF: 0.00 AC: 0 AN: 33228

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.32
DANN	Benign	0.69
PhyloP100		-0.42

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;