11-121496917-T-C

Variant names:

• chr11-121496917-T-C
• rs12364988
• NM_003105.6:c.807T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003105.6(SORL1):​c.807T>C​(p.His269His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.5 in 1,612,730 control chromosomes in the GnomAD database, including 203,278 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19579 hom., cov: 29)
  • Exomes 𝑓: 0.50 (183699 hom.)
• Consequence: SORL1 NM_003105.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.01
• Publications: 42 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 11-121496917-T-C is Benign according to our data. Variant chr11-121496917-T-C is described in ClinVar as Benign. ClinVar VariationId is 1209921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.532 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.807T>C	p.His269His	synonymous	Exon 6 of 48	NP_003096.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	ENST00000260197.12	TSL:1 MANE Select	c.807T>C	p.His269His	synonymous	Exon 6 of 48	ENSP00000260197.6
	SORL1	ENST00000532451.1	TSL:1	n.759T>C		non_coding_transcript_exon	Exon 6 of 15
	SORL1	ENST00000905166.1		c.807T>C	p.His269His	synonymous	Exon 6 of 48	ENSP00000575225.1

Frequencies

GnomAD3 genomes AF: 0.505 AC: 76419 AN: 151450 Hom.: 19563 Cov.: 29

Gnomad AFR AF: 0.503

Gnomad AMI AF: 0.657

Gnomad AMR AF: 0.542

Gnomad ASJ AF: 0.628

Gnomad EAS AF: 0.313

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.479

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.513

GnomAD2 exomes AF: 0.489 AC: 122852 AN: 251272 AF XY: 0.489

Gnomad AFR exome AF: 0.497

Gnomad AMR exome AF: 0.490

Gnomad ASJ exome AF: 0.614

Gnomad EAS exome AF: 0.313

Gnomad FIN exome AF: 0.486

Gnomad NFE exome AF: 0.514

Gnomad OTH exome AF: 0.532

GnomAD4 exome AF: 0.500 AC: 730112 AN: 1461162 Hom.: 183699 Cov.: 38 AF XY: 0.499 AC XY: 362797 AN XY: 726940

African (AFR) AF: 0.500 AC: 16727 AN: 33464

American (AMR) AF: 0.497 AC: 22211 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.619 AC: 16173 AN: 26132

East Asian (EAS) AF: 0.329 AC: 13057 AN: 39690

South Asian (SAS) AF: 0.454 AC: 39156 AN: 86238

European-Finnish (FIN) AF: 0.491 AC: 26231 AN: 53374

Middle Eastern (MID) AF: 0.599 AC: 3455 AN: 5766

European-Non Finnish (NFE) AF: 0.506 AC: 562623 AN: 1111410

Other (OTH) AF: 0.505 AC: 30479 AN: 60368

GnomAD4 genome AF: 0.505 AC: 76471 AN: 151568 Hom.: 19579 Cov.: 29 AF XY: 0.505 AC XY: 37415 AN XY: 74042

African (AFR) AF: 0.504 AC: 20786 AN: 41258

American (AMR) AF: 0.542 AC: 8257 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.628 AC: 2178 AN: 3466

East Asian (EAS) AF: 0.312 AC: 1610 AN: 5158

South Asian (SAS) AF: 0.435 AC: 2084 AN: 4790

European-Finnish (FIN) AF: 0.479 AC: 5023 AN: 10476

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.511 AC: 34688 AN: 67876

Other (OTH) AF: 0.507 AC: 1064 AN: 2098

Alfa AF: 0.512 Hom.: 80816

Bravo AF: 0.507

Asia WGS AF: 0.372 AC: 1295 AN: 3478

EpiCase AF: 0.528

EpiControl AF: 0.519

ClinVar

ClinVar submissions as Germline

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

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.74
DANN	Benign	0.63
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=95/5	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: rs12364988; hg19: chr11-121367626; COSMIC: COSV52751349;