10-104641362-G-A

Position:

• chr10-104641362-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_014978.3(SORCS3):​c.35G>A​(p.Arg12Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00482 in 1,408,960 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (28 hom.)
• Consequence: SORCS3 NM_014978.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.29

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037207603).
• BP6: Variant 10-104641362-G-A is Benign according to our data. Variant chr10-104641362-G-A is described in ClinVar as [Benign]. Clinvar id is 721118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SORCS3	NM_014978.3	c.35G>A	p.Arg12Lys	missense_variant	1/27	ENST00000369701.8	NP_055793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SORCS3	ENST00000369701.8	c.35G>A	p.Arg12Lys	missense_variant	1/27	1	NM_014978.3	ENSP00000358715	P1

Frequencies

GnomAD3 genomes AF: 0.00466 AC: 708 AN: 151852 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.0253

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00636

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00492 AC: 250 AN: 50800 Hom.: 1 AF XY: 0.00462 AC XY: 139 AN XY: 30094

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000734

Gnomad ASJ exome AF: 0.00969

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000267

Gnomad FIN exome AF: 0.0121

Gnomad NFE exome AF: 0.00744

Gnomad OTH exome AF: 0.00346

GnomAD4 exome AF: 0.00484 AC: 6084 AN: 1257000 Hom.: 28 Cov.: 31 AF XY: 0.00471 AC XY: 2907 AN XY: 616564

Gnomad4 AFR exome AF: 0.000595

Gnomad4 AMR exome AF: 0.000669

Gnomad4 ASJ exome AF: 0.00988

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000274

Gnomad4 FIN exome AF: 0.0143

Gnomad4 NFE exome AF: 0.00508

Gnomad4 OTH exome AF: 0.00417

GnomAD4 genome AF: 0.00466 AC: 708 AN: 151960 Hom.: 3 Cov.: 32 AF XY: 0.00509 AC XY: 378 AN XY: 74290

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.000590

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0163

Gnomad4 NFE AF: 0.00636

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00389 Hom.: 0

Bravo AF: 0.00333

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ExAC AF: 0.00169 AC: 90

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.012	T;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.24	.;T
MetaRNN	Benign	0.0037	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.020	N;.
REVEL	Benign	0.040
Sift	Benign	1.0	T;.
Sift4G	Benign	0.85	T;T
Polyphen		0.0090	B;B
Vest4		0.19
MVP		0.30
MPC		0.34
ClinPred		0.022	T
GERP RS		3.4
Varity_R		0.17
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs562822100; hg19: chr10-106401120;