chr11-121452363-G-C

Variant names:

• chr11-121452363-G-C
• rs147575757
• NM_003105.6:c.32G>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_003105.6(SORL1):​c.32G>C​(p.Arg11Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000461 in 1,552,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (0 hom.)
• Consequence: SORL1 NM_003105.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.22
• 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18536413).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000309 (47/152050) while in subpopulation NFE AF = 0.000677 (46/67974). AF 95% confidence interval is 0.000521. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 47 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.32G>C	p.Arg11Pro	missense	Exon 1 of 48	NP_003096.2	Q92673
	SORL1-AS1	NR_183636.1	MANE Select	n.293+312C>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.32G>C	p.Arg11Pro	missense	Exon 1 of 48	ENSP00000260197.6	Q92673
	SORL1-AS1	ENST00000529160.2	TSL:2 MANE Select	n.293+312C>G		intron	N/A
	SORL1	ENST00000905166.1		c.32G>C	p.Arg11Pro	missense	Exon 1 of 48	ENSP00000575225.1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152050 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000677

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000142 AC: 23 AN: 162290 AF XY: 0.000144

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000383

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000322

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000478 AC: 669 AN: 1400830 Hom.: 0 Cov.: 30 AF XY: 0.000436 AC XY: 303 AN XY: 694200

African (AFR) AF: 0.0000696 AC: 2 AN: 28742

American (AMR) AF: 0.00 AC: 0 AN: 37766

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24464

East Asian (EAS) AF: 0.00 AC: 0 AN: 33224

South Asian (SAS) AF: 0.00 AC: 0 AN: 79092

European-Finnish (FIN) AF: 0.0000202 AC: 1 AN: 49536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4192

European-Non Finnish (NFE) AF: 0.000573 AC: 622 AN: 1086116

Other (OTH) AF: 0.000763 AC: 44 AN: 57698

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152050 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74290

African (AFR) AF: 0.0000241 AC: 1 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000677 AC: 46 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000325 Hom.: 0

Bravo AF: 0.000257

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000702 AC: 6

ExAC AF: 0.000152 AC: 18

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	0.12
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.080	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.2
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.83	N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.045	D
Polyphen		0.0	B
Vest4		0.40
MVP		0.74
MPC		0.36
ClinPred		0.25	T
GERP RS		1.9
PromoterAI		0.0041	Neutral
Varity_R		0.50
gMVP		0.44
Mutation Taster		=81/19	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: rs147575757; hg19: chr11-121323072; COSMIC: COSV99036296; COSMIC: COSV99036296;