chr11-121577381-T-G

Variant names:

• chr11-121577381-T-G
• rs2070045
• NM_003105.6:c.3561T>G
• SORL1 p.Ser1187Ser

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -17 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_StrongBP7

The NM_003105.6(SORL1):c.3561T>G (p.Ser1187Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.254 (AC=409,496) in the gnomAD database across 1,609,520 control chromosomes, including 59,433 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.547. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5264 hom., cov: 33)
  • Exomes 𝑓: 0.26 (54169 hom.)
• Consequence: SORL1 NM_003105.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.19
• Publications: 77 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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -17 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.5470 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SORL1 NM_003105.6	MANE Select	c.3561T>G p.Ser1187Ser	synonymous	Exon 25 of 48	Prot: NP_003096.2 UniProt:

SORL1 NM_003105.6

MANE Select

HGVSc / HGVSpc.3561T>Gp.Ser1187Ser

Exon rankExon 25 of 48

synonymous

Prot: NP_003096.2UniProt: Q92673

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SORL1 ENST00000260197.12	TSL:1MANE Select	c.3561T>G p.Ser1187Ser	synonymous	Exon 25 of 48	Prot: ENSP00000260197.6 UniProt:
	SORL1 ENST00000905166.1		c.3561T>G p.Ser1187Ser	synonymous	Exon 25 of 48	Prot: ENSP00000575225.1 UniProt:
	SORL1 ENST00000905167.1		c.3444T>G p.Ser1148Ser	synonymous	Exon 24 of 47	Prot: ENSP00000575226.1 UniProt:

SORL1 ENST00000260197.12

TSL:1MANE Select

HGVSc / HGVSpc.3561T>Gp.Ser1187Ser

Exon rankExon 25 of 48

synonymous

Prot: ENSP00000260197.6UniProt: Q92673

SORL1 ENST00000905166.1

HGVSc / HGVSpc.3561T>Gp.Ser1187Ser

Exon rankExon 25 of 48

synonymous

Prot: ENSP00000575225.1UniProt: A0ACI8RW67

SORL1 ENST00000905167.1

HGVSc / HGVSpc.3444T>Gp.Ser1148Ser

Exon rankExon 24 of 47

synonymous

Prot: ENSP00000575226.1UniProt: A0ACI8S861

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.234	AC:35590	Hom:5241	AN:152042	Cov:33
GnomAD2 exomes	AF: 0.321	AC:79110	Hom:	AN:246584	Cov:
GnomAD4 exome	AF: 0.257	AC:373866	Hom:54169	AN:1457360	Cov:33
GnomAD4 genome	AF: 0.234	AC:35630	Hom:5264	AN:152160	Cov:33
TOPMed (Bravo)	AF: 0.236	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.232	AC:76234	Hom:9682	AN:328640	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.263	AC:617	Hom:93	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.579	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.203	AC:61	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.188	AC:2439	Hom:	AN:13004	Cov:
GenomeAsia100K	AF: 0.505	AC:1755	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.514	AC:3720	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.265	AC:533	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.470	AC:57696	Hom:13528	AN:122792	Cov:
Turkish Variome	AF: 0.276	AC:1854	Hom:279	AN:6722	Cov:
UK10K	AF: 0.237	AC:1793	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.583	AC:5222	Hom:1539	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.250 *	2743	10982	0.247 *	4320	17486
BipEx(Bipolar disorder (including schizoaffective))	0.232	6592	28380	0.234	6736	28736
Epi25(Epilepsy)	0.252	10554	41866	0.253	16895	66672
SCHEMA(Schizophrenia)	0.348	51708	148500	0.337	85655	254484

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	SORL1-related disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.16
BayesDel_noAF	Benign	-0.59
CADD	Benign	4.0
DANN	Benign	0.72
GPN-Star LLR	N/A	-3.3
GPN-Star score	N/A	3.3
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-1.2

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs2070045;

hg19: chr11-121448090;

COSMIC: COSV52749539;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar