11-121452532-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_003105.6(SORL1):c.201G>C(p.Arg67Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000273 in 1,488,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. R67R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: SORL1 NM_003105.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048567474).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000223 (34/152266) while in subpopulation EAS AF= 0.000388 (2/5158). AF 95% confidence interval is 0.000194. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORL1	NM_003105.6	c.201G>C	p.Arg67Ser	missense_variant	1/48	ENST00000260197.12
SORL1-AS1	NR_183636.1	n.293+143C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORL1	ENST00000260197.12	c.201G>C	p.Arg67Ser	missense_variant	1/48	1	NM_003105.6	P1
SORL1	ENST00000532451.1	n.153G>C		non_coding_transcript_exon_variant	1/15	1
SORL1-AS1	ENST00000501964.1	n.339+143C>G		intron_variant, non_coding_transcript_variant		2
SORL1-AS1	ENST00000529160.1	n.245+143C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000617 AC: 6 AN: 97182 Hom.: 0 AF XY: 0.0000361 AC XY: 2 AN XY: 55390

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000588

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000279 AC: 373 AN: 1336060 Hom.: 0 Cov.: 31 AF XY: 0.000264 AC XY: 174 AN XY: 658198

Gnomad4 AFR exome AF: 0.000183

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000323

Gnomad4 SAS exome AF: 0.000149

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000321

Gnomad4 OTH exome AF: 0.000307

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74452

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000387 Hom.: 0

Bravo AF: 0.000193

ExAC AF: 0.0000352 AC: 4

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

Invitae

Nov 17, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This missense change has been observed in individual(s) with Alzheimer disease (PMID: 33879716). This variant is present in population databases (rs556756459, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 67 of the SORL1 protein (p.Arg67Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	15
Dann	Uncertain	0.98
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.36	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	0.98	N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.26	N
REVEL	Uncertain	0.29
Sift	Benign	0.75	T
Sift4G	Benign	0.16	T
Polyphen		0.0010	B
Vest4		0.083
MutPred		0.21		Gain of glycosylation at R67 (P = 0.0097);
MVP		0.65
MPC		0.28
ClinPred		0.068	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.43

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: rs556756459; hg19: chr11-121323241;