10-104641461-G-T

Variant names:

• chr10-104641461-G-T
• rs910479980
• NM_014978.3:c.134G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014978.3(SORCS3):​c.134G>T​(p.Arg45Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000341 in 1,466,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. R45H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: SORCS3 NM_014978.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.132
• Publications: 0 publications found

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]

SORCS3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062354982).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS3	NM_014978.3	c.134G>T	p.Arg45Leu	missense_variant	Exon 1 of 27	ENST00000369701.8	NP_055793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORCS3	ENST00000369701.8	c.134G>T	p.Arg45Leu	missense_variant	Exon 1 of 27	1	NM_014978.3	ENSP00000358715.3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152004 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000304 AC: 4 AN: 1314488 Hom.: 0 Cov.: 31 AF XY: 0.00000309 AC XY: 2 AN XY: 647414

African (AFR) AF: 0.00 AC: 0 AN: 26490

American (AMR) AF: 0.00 AC: 0 AN: 24860

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23168

East Asian (EAS) AF: 0.00 AC: 0 AN: 28156

South Asian (SAS) AF: 0.00 AC: 0 AN: 72078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4054

European-Non Finnish (NFE) AF: 0.00000382 AC: 4 AN: 1048472

Other (OTH) AF: 0.00 AC: 0 AN: 54414

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152004 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74258

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15262

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67958

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	14
DANN	Benign	0.74
DEOGEN2	Benign	0.011	T;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.58	.;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.062	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N;N
PhyloP100		-0.13
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.24	N;.
REVEL	Benign	0.023
Sift	Benign	0.34	T;.
Sift4G	Benign	0.16	T;T
Polyphen		0.0	B;B
Vest4		0.071
MutPred		0.31		Loss of methylation at R45 (P = 0.0127);Loss of methylation at R45 (P = 0.0127);
MVP		0.31
MPC		0.42
ClinPred		0.061	T
GERP RS		2.2
PromoterAI		0.00060	Neutral
Varity_R		0.066
gMVP		0.26
Mutation Taster		=97/3	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: rs910479980; hg19: chr10-106401219;