10-104641421-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_014978.3(SORCS3):c.94G>A(p.Gly32Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,467,680 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0067 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (4 hom.)
• Consequence: SORCS3 NM_014978.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.33

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00376907).
• BP6: Variant 10-104641421-G-A is Benign according to our data. Variant chr10-104641421-G-A is described in ClinVar as [Benign]. Clinvar id is 786584.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00669 (1017/152082) while in subpopulation AFR AF= 0.0231 (958/41528). AF 95% confidence interval is 0.0219. There are 12 homozygotes in gnomad4. There are 482 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SORCS3	NM_014978.3	c.94G>A	p.Gly32Ser	missense_variant	1/27	ENST00000369701.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SORCS3	ENST00000369701.8	c.94G>A	p.Gly32Ser	missense_variant	1/27	1	NM_014978.3	P1

Frequencies

GnomAD3 genomes AF: 0.00667 AC: 1013 AN: 151974 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

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: 0.000147

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000741 AC: 56 AN: 75564 Hom.: 0 AF XY: 0.000666 AC XY: 29 AN XY: 43562

Gnomad AFR exome AF: 0.0266

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000252

Gnomad OTH exome AF: 0.000459

GnomAD4 exome AF: 0.000604 AC: 795 AN: 1315598 Hom.: 4 Cov.: 31 AF XY: 0.000521 AC XY: 338 AN XY: 648496

Gnomad4 AFR exome AF: 0.0213

Gnomad4 AMR exome AF: 0.00193

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000554

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000725

Gnomad4 OTH exome AF: 0.00163

GnomAD4 genome AF: 0.00669 AC: 1017 AN: 152082 Hom.: 12 Cov.: 32 AF XY: 0.00648 AC XY: 482 AN XY: 74356

Gnomad4 AFR AF: 0.0231

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00492 Hom.: 1

Bravo AF: 0.00736

ESP6500AA AF: 0.0120 AC: 31

ESP6500EA AF: 0.000728 AC: 4

ExAC AF: 0.000798 AC: 58

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.015	T;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.28	N
MetaRNN	Benign	0.0038	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	0.98	N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.83	N;.
REVEL	Benign	0.024
Sift	Uncertain	0.022	D;.
Sift4G	Benign	0.12	T;T
Polyphen		0.46	P;P
Vest4		0.31
MVP		0.29
MPC		1.0
ClinPred		0.042	T
GERP RS		3.3
Varity_R		0.091
gMVP		0.24

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: rs143668607; hg19: chr10-106401179;