11-121590137-C-T

Variant names:

• chr11-121590137-C-T
• rs2276412
• NM_003105.6:c.4176C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_003105.6(SORL1):​c.4176C>T​(p.Asn1392Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0273 in 1,614,016 control chromosomes in the GnomAD database, including 1,801 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (767 hom., cov: 33)
  • Exomes 𝑓: 0.023 (1034 hom.)
• Consequence: SORL1 NM_003105.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.37
• Publications: 28 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 11-121590137-C-T is Benign according to our data. Variant chr11-121590137-C-T is described in ClinVar as Benign. ClinVar VariationId is 1600983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	NM_003105.6	MANE Select	c.4176C>T	p.Asn1392Asn	synonymous	Exon 30 of 48	NP_003096.2	Q92673

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	ENST00000260197.12	TSL:1 MANE Select	c.4176C>T	p.Asn1392Asn	synonymous	Exon 30 of 48	ENSP00000260197.6	Q92673
	SORL1	ENST00000905166.1		c.4176C>T	p.Asn1392Asn	synonymous	Exon 30 of 48	ENSP00000575225.1
	SORL1	ENST00000905167.1		c.4059C>T	p.Asn1353Asn	synonymous	Exon 29 of 47	ENSP00000575226.1

Frequencies

GnomAD3 genomes AF: 0.0667 AC: 10146 AN: 152112 Hom.: 767 Cov.: 33

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0349

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.0645

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.00801

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0181

Gnomad OTH AF: 0.0488

GnomAD2 exomes AF: 0.0317 AC: 7984 AN: 251474 AF XY: 0.0284

Gnomad AFR exome AF: 0.195

Gnomad AMR exome AF: 0.0162

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.0561

Gnomad FIN exome AF: 0.00919

Gnomad NFE exome AF: 0.0185

Gnomad OTH exome AF: 0.0202

GnomAD4 exome AF: 0.0232 AC: 33874 AN: 1461786 Hom.: 1034 Cov.: 31 AF XY: 0.0225 AC XY: 16387 AN XY: 727202

African (AFR) AF: 0.195 AC: 6531 AN: 33460

American (AMR) AF: 0.0177 AC: 790 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0122 AC: 318 AN: 26136

East Asian (EAS) AF: 0.0790 AC: 3138 AN: 39698

South Asian (SAS) AF: 0.0214 AC: 1850 AN: 86258

European-Finnish (FIN) AF: 0.00867 AC: 463 AN: 53418

Middle Eastern (MID) AF: 0.0265 AC: 153 AN: 5768

European-Non Finnish (NFE) AF: 0.0170 AC: 18944 AN: 1111940

Other (OTH) AF: 0.0279 AC: 1687 AN: 60384

GnomAD4 genome AF: 0.0667 AC: 10157 AN: 152230 Hom.: 767 Cov.: 33 AF XY: 0.0646 AC XY: 4807 AN XY: 74450

African (AFR) AF: 0.186 AC: 7732 AN: 41504

American (AMR) AF: 0.0349 AC: 534 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3470

East Asian (EAS) AF: 0.0649 AC: 336 AN: 5178

South Asian (SAS) AF: 0.0178 AC: 86 AN: 4824

European-Finnish (FIN) AF: 0.00801 AC: 85 AN: 10614

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0181 AC: 1228 AN: 68018

Other (OTH) AF: 0.0483 AC: 102 AN: 2112

Alfa AF: 0.0362 Hom.: 465

Bravo AF: 0.0738

Asia WGS AF: 0.0470 AC: 162 AN: 3478

EpiCase AF: 0.0188

EpiControl AF: 0.0205

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	6.1
DANN	Benign	0.85
PhyloP100		-1.4
PromoterAI		-0.044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs2276412; hg19: chr11-121460846; COSMIC: COSV52755768; COSMIC: COSV52755768;