11-121452468-G-C

Variant names:

• chr11-121452468-G-C
• rs949112777
• NM_003105.6:c.137G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_003105.6(SORL1):​c.137G>C​(p.Arg46Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000458 in 1,353,758 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R46G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: SORL1 NM_003105.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.87
• 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-AS1 (HGNC:55594): (SORL1 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 62 AD gene.

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.137G>C	p.Arg46Pro	missense	Exon 1 of 48	NP_003096.2	Q92673
	SORL1-AS1	NR_183636.1	MANE Select	n.293+207C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	ENST00000260197.12	TSL:1 MANE Select	c.137G>C	p.Arg46Pro	missense	Exon 1 of 48	ENSP00000260197.6	Q92673
	SORL1	ENST00000532451.1	TSL:1	n.89G>C		non_coding_transcript_exon	Exon 1 of 15
	SORL1-AS1	ENST00000529160.2	TSL:2 MANE Select	n.293+207C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000458 AC: 62 AN: 1353758 Hom.: 0 Cov.: 31 AF XY: 0.0000525 AC XY: 35 AN XY: 666282

African (AFR) AF: 0.00 AC: 0 AN: 27516

American (AMR) AF: 0.00 AC: 0 AN: 30908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23744

East Asian (EAS) AF: 0.00 AC: 0 AN: 30740

South Asian (SAS) AF: 0.00 AC: 0 AN: 75500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44754

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4378

European-Non Finnish (NFE) AF: 0.0000575 AC: 61 AN: 1060326

Other (OTH) AF: 0.0000179 AC: 1 AN: 55892

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.0088
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	0.096	D
MutationAssessor	Benign	1.1	L
PhyloP100		2.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.41	N
REVEL	Uncertain	0.52
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.10	B
Vest4		0.50
MutPred		0.61		Gain of glycosylation at R46 (P = 0.0857)
MVP		0.84
MPC		0.39
ClinPred		0.88	D
GERP RS		3.9
PromoterAI		-0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.73
gMVP		0.70
Mutation Taster		=72/28	polymorphism

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: rs949112777; hg19: chr11-121323177;