11-121452467-C-T

Variant names:

• chr11-121452467-C-T
• rs200826396
• NM_003105.6:c.136C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003105.6(SORL1):​c.136C>T​(p.Arg46Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000738 in 1,354,922 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: 7.4e-7 (0 hom.)
• Consequence: SORL1 NM_003105.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.31
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

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

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.136C>T	p.Arg46Trp	missense	Exon 1 of 48	NP_003096.2	Q92673
	SORL1-AS1	NR_183636.1	MANE Select	n.293+208G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SORL1	ENST00000260197.12	TSL:1 MANE Select	c.136C>T	p.Arg46Trp	missense	Exon 1 of 48	ENSP00000260197.6	Q92673
	SORL1	ENST00000532451.1	TSL:1	n.88C>T		non_coding_transcript_exon	Exon 1 of 15
	SORL1-AS1	ENST00000529160.2	TSL:2 MANE Select	n.293+208G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000934 AC: 1 AN: 107116 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000250

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.38e-7 AC: 1 AN: 1354922 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 666908

African (AFR) AF: 0.00 AC: 0 AN: 27562

American (AMR) AF: 0.00 AC: 0 AN: 31012

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23794

East Asian (EAS) AF: 0.00 AC: 0 AN: 30784

South Asian (SAS) AF: 0.00 AC: 0 AN: 75586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4366

European-Non Finnish (NFE) AF: 9.43e-7 AC: 1 AN: 1060934

Other (OTH) AF: 0.00 AC: 0 AN: 55944

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000952 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.083
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.8	L
PhyloP100		1.3
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.91	P
Vest4		0.34
MutPred		0.68		Loss of disorder (P = 0.0126)
MVP		0.87
MPC		0.26
ClinPred		0.88	D
GERP RS		3.9
PromoterAI		-0.044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.57
gMVP		0.56
Mutation Taster		=75/25	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: rs200826396; hg19: chr11-121323176;