chr11-121452468-G-C

Position:

• chr11-121452468-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

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

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORL1	NM_003105.6	c.137G>C	p.Arg46Pro	missense_variant	1/48	ENST00000260197.12
SORL1-AS1	NR_183636.1	n.293+207C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORL1	ENST00000260197.12	c.137G>C	p.Arg46Pro	missense_variant	1/48	1	NM_003105.6	P1
SORL1	ENST00000532451.1	n.89G>C		non_coding_transcript_exon_variant	1/15	1
SORL1-AS1	ENST00000501964.1	n.339+207C>G		intron_variant, non_coding_transcript_variant		2
SORL1-AS1	ENST00000529160.1	n.245+207C>G		intron_variant, non_coding_transcript_variant		2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000575

Gnomad4 OTH exome AF: 0.0000179

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 25, 2023

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 46 of the SORL1 protein (p.Arg46Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SORL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1509841). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.79	D
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.73
gMVP		0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs949112777; hg19: chr11-121323177;