22-30287384-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_001037666.3(CASTOR1):​c.361G>T​(p.Asp121Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CASTOR1
NM_001037666.3 missense

Scores

9
7
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.90
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a mutagenesis_site No effect on arginine-binding. No effect on homodimerization. Loss of interaction with the GATOR2 complex which constitutively activates the TORC1 signaling pathway. (size 0) in uniprot entity CAST1_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CASTOR1NM_001037666.3 linkc.361G>T p.Asp121Tyr missense_variant Exon 3 of 9 ENST00000407689.8 NP_001032755.1 Q8WTX7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CASTOR1ENST00000407689.8 linkc.361G>T p.Asp121Tyr missense_variant Exon 3 of 9 1 NM_001037666.3 ENSP00000384183.4 Q8WTX7
ENSG00000248751ENST00000434291.5 linkc.928G>T p.Asp310Tyr missense_variant Exon 8 of 13 2 ENSP00000401535.1 H7C1Q1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000343
AC:
5
AN:
1459500
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
725900
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000672
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 22, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.361G>T (p.D121Y) alteration is located in exon 3 (coding exon 3) of the GATSL3 gene. This alteration results from a G to T substitution at nucleotide position 361, causing the aspartic acid (D) at amino acid position 121 to be replaced by a tyrosine (Y). 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
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.17
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.53
D;T;.
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.96
D;D;D
MetaSVM
Uncertain
-0.23
T
PROVEAN
Pathogenic
-7.3
D;D;N
REVEL
Pathogenic
0.69
Sift
Uncertain
0.0010
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;D;.
Vest4
0.99
MutPred
0.88
Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);.;
MVP
0.75
MPC
1.6
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.93
gMVP
0.97

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.

Other links and lift over

dbSNP: rs1020524089; hg19: chr22-30683373; API