Genetic Variant CASTOR1:p.Arg322Gln (chr22-30285645-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001037666.3(CASTOR1):c.965G>A(p.Arg322Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000433 in 1,570,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

CASTOR1
NM_001037666.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.09

Variant links:

Genes affected

CASTOR1 (HGNC:34423): (cytosolic arginine sensor for mTORC1 subunit 1) Enables arginine binding activity and identical protein binding activity. Involved in cellular response to L-arginine and negative regulation of TORC1 signaling. Located in cytosol. Colocalizes with GATOR2 complex. [provided by Alliance of Genome Resources, Apr 2022]

CASTOR1 links:

ENSG00000248751 (HGNC:):

ENSG00000248751 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.0075908005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASTOR1	NM_001037666.3 link	c.965G>A	p.Arg322Gln	missense_variant	Exon 9 of 9	ENST00000407689.8	NP_001032755.1	Q8WTX7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASTOR1	ENST00000407689.8 link	c.965G>A	p.Arg322Gln	missense_variant	Exon 9 of 9	1	NM_001037666.3	ENSP00000384183.4		Q8WTX7
ENSG00000248751	ENST00000434291.5 link	c.1418G>A	p.Arg473Gln	missense_variant	Exon 13 of 13	2		ENSP00000401535.1		H7C1Q1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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

GnomAD3 exomes

AF:

0.000105

AC:

AN:

181320

Hom.:

AF XY:

0.000112

AC XY:

AN XY:

98452

show subpopulations

Gnomad AFR exome

AF:

0.000618

Gnomad AMR exome

AF:

0.000322

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000122

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000261

AC:

AN:

1417862

Hom.:

Cov.:

AF XY:

0.0000228

AC XY:

AN XY:

701726

show subpopulations

Gnomad4 AFR exome

AF:

0.000308

Gnomad4 AMR exome

AF:

0.000333

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000743

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000642

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.000204

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000674

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000191

Hom.:

Bravo

AF:

0.000212

ExAC

AF:

0.0000594

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.965G>A (p.R322Q) alteration is located in exon 9 (coding exon 9) of the GATSL3 gene. This alteration results from a G to A substitution at nucleotide position 965, causing the arginine (R) at amino acid position 322 to be replaced by a glutamine (Q). 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

0.059

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.73

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0040

T;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.70

T;T;T

M_CAP

Benign

0.0050

MetaRNN

Benign

0.0076

T;T;T

MetaSVM

Benign

-0.92

PROVEAN

Benign

0.18

N;N;N

REVEL

Benign

0.023

Sift

Benign

0.34

T;T;T

Sift4G

Benign

0.60

T;T;T

Polyphen

0.0010

B;B;.

Vest4

0.11

MVP

0.13

MPC

0.58

ClinPred

0.017

GERP RS

0.61

Varity_R

0.11

gMVP

0.21

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over