10-104641850-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014978.3(SORCS3):c.523G>A(p.Gly175Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,571,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: SORCS3 NM_014978.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.82

Genes affected

SORCS3 (HGNC:16699): (sortilin related VPS10 domain containing receptor 3) This gene encodes a type-I receptor transmembrane protein that is a member of the vacuolar protein sorting 10 receptor family. Proteins of this family are defined by a vacuolar protein sorting 10 domain at the N-terminus. The N-terminal segment of this domain has a consensus motif for proprotein convertase processing, and the C-terminal segment of this domain is characterized by ten conserved cysteine residues. The vacuolar protein sorting 10 domain is followed by a leucine-rich segment, a transmembrane domain, and a short C-terminal cytoplasmic domain that interacts with adaptor molecules. The transcript is expressed at high levels in the brain, and candidate gene studies suggest that genetic variation in this gene is associated with Alzheimer's disease. Consistent with this observation, knockdown of the gene in cell culture results in an increase in amyloid precursor protein processing. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.006566018).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORCS3	NM_014978.3	c.523G>A	p.Gly175Arg	missense_variant	1/27	ENST00000369701.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORCS3	ENST00000369701.8	c.523G>A	p.Gly175Arg	missense_variant	1/27	1	NM_014978.3	P1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000161 AC: 28 AN: 174396 Hom.: 0 AF XY: 0.000178 AC XY: 17 AN XY: 95772

Gnomad AFR exome AF: 0.000112

Gnomad AMR exome AF: 0.000106

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000407

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000412

Gnomad OTH exome AF: 0.000422

GnomAD4 exome AF: 0.000102 AC: 145 AN: 1418816 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 76 AN XY: 702356

Gnomad4 AFR exome AF: 0.0000616

Gnomad4 AMR exome AF: 0.000278

Gnomad4 ASJ exome AF: 0.00267

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000311

Gnomad4 OTH exome AF: 0.000357

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74478

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000322 Hom.: 0

Bravo AF: 0.000536

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000244 AC: 2

ExAC AF: 0.000110 AC: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2022

The c.523G>A (p.G175R) alteration is located in exon 1 (coding exon 1) of the SORCS3 gene. This alteration results from a G to A substitution at nucleotide position 523, causing the glycine (G) at amino acid position 175 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	20
Dann	Benign	0.91
DEOGEN2	Benign	0.011	T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.71
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.0066	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	0.90	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.53	N;.
REVEL	Benign	0.033
Sift	Benign	0.74	T;.
Sift4G	Benign	0.39	T;T
Polyphen		0.0010	B;B
Vest4		0.32
MutPred		0.26		Gain of MoRF binding (P = 0.0096);Gain of MoRF binding (P = 0.0096);
MVP		0.49
MPC		0.44
ClinPred		0.0084	T
GERP RS		3.3
Varity_R		0.081
gMVP		0.46

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: rs375217719; hg19: chr10-106401608;