NM_003105.6:c.4752T>A

Variant names:

• chr11-121605213-T-A
• rs3824968
• NM_003105.6:c.4752T>A
• SORL1 p.Ala1584Ala

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.4752T>A (p.Ala1584Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.332 (AC=535,983) in the gnomAD database across 1,612,564 control chromosomes, including 95,938 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.573. 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 0.30 (8106 hom., cov: 32)
  • Exomes 𝑓: 0.34 (87832 hom.)
• Consequence: SORL1 NM_003105.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.284
• Publications: 2 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 = 0.5725 — 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.4752T>A p.Ala1584Ala	synonymous	Exon 34 of 48	Prot: NP_003096.2 UniProt:

SORL1 NM_003105.6

MANE Select

HGVSc / HGVSpc.4752T>Ap.Ala1584Ala

Exon rankExon 34 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.4752T>A p.Ala1584Ala	synonymous	Exon 34 of 48	Prot: ENSP00000260197.6 UniProt:
	SORL1 ENST00000905166.1		c.4752T>A p.Ala1584Ala	synonymous	Exon 34 of 48	Prot: ENSP00000575225.1 UniProt:
	SORL1 ENST00000905167.1		c.4635T>A p.Ala1545Ala	synonymous	Exon 33 of 47	Prot: ENSP00000575226.1 UniProt:

SORL1 ENST00000260197.12

TSL:1MANE Select

HGVSc / HGVSpc.4752T>Ap.Ala1584Ala

Exon rankExon 34 of 48

synonymous

Prot: ENSP00000260197.6UniProt: Q92673

SORL1 ENST00000905166.1

HGVSc / HGVSpc.4752T>Ap.Ala1584Ala

Exon rankExon 34 of 48

synonymous

Prot: ENSP00000575225.1UniProt: A0ACI8RW67

SORL1 ENST00000905167.1

HGVSc / HGVSpc.4635T>Ap.Ala1545Ala

Exon rankExon 33 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: 0.302	AC:45901	Hom:8086	AN:151984	Cov:32
GnomAD2 exomes	AF: 0.389	AC:97703	Hom:	AN:250848	Cov:
GnomAD4 exome	AF: 0.336	AC:490019	Hom:87832	AN:1460462	Cov:35
GnomAD4 genome	AF: 0.302	AC:45964	Hom:8106	AN:152102	Cov:32
TOPMed (Bravo)	AF: 0.297	AC:78556	Hom:13692	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.297	AC:16577	Hom:2605	AN:55756	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.312	AC:730	Hom:124	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.604	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.300	AC:90	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.255	AC:3315	Hom:	AN:13004	Cov:
GenomeAsia100K	AF: 0.536	AC:1865	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.533	AC:3854	Hom:	AN:7232	Cov:
Qatari Genome	AF: 0.364	AC:732	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.488	AC:59946	Hom:14562	AN:122774	Cov:
Turkish Variome	AF: 0.367	AC:2467	Hom:473	AN:6724	Cov:
UK10K	AF: 0.314	AC:2378	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.601	AC:5389	Hom:1642	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.322 *	3552	11020	0.319 *	5598	17536
BipEx(Bipolar disorder (including schizoaffective))	0.315	8941	28418	0.314	9057	28832
Epi25(Epilepsy)	0.329	13797	41952	0.326	21828	66870
SCHEMA(Schizophrenia)	0.404	61880	153184	0.392	103417	263694

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	3.7
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.7
DANN	Benign	0.65
GPN-Star LLR	N/A	-3.2
GPN-Star score	N/A	3.2
Mutation Taster	N/A	98/2	polymorphism (auto)
PhyloP100	Benign	0.28

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: rs3824968;

hg19: chr11-121475922;

COSMIC: COSV52749563;

COSMIC: COSV52749563;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar