12-113191419-C-T

Variant summary

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

The NM_032848.3(RITA1):​c.412C>T​(p.Arg138Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000059 in 1,609,536 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

RITA1
NM_032848.3 missense

Scores

4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.73
Variant links:
Genes affected
RITA1 (HGNC:25925): (RBPJ interacting and tubulin associated 1) Enables tubulin binding activity. Involved in negative regulation of Notch signaling pathway and nuclear export. Located in centrosome; cytoplasm; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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=0.052532643).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RITA1NM_032848.3 linkc.412C>T p.Arg138Cys missense_variant Exon 4 of 4 ENST00000548278.2 NP_116237.1 Q96K30-1A0A024RBL1
RITA1NM_001286215.2 linkc.484C>T p.Arg162Cys missense_variant Exon 3 of 3 NP_001273144.1 Q96K30-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RITA1ENST00000548278.2 linkc.412C>T p.Arg138Cys missense_variant Exon 4 of 4 1 NM_032848.3 ENSP00000449841.1 Q96K30-1
RITA1ENST00000552495.1 linkc.484C>T p.Arg162Cys missense_variant Exon 3 of 3 2 ENSP00000448680.1 Q96K30-3
RITA1ENST00000549621.5 linkc.412C>T p.Arg138Cys missense_variant Exon 4 of 4 2 ENSP00000448289.1 Q96K30-1
ENSG00000257286ENST00000552525.1 linkn.69+674G>A intron_variant Intron 1 of 1 3

Frequencies

GnomAD3 genomes
AF:
0.0000789
AC:
12
AN:
152154
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.000162
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000482
AC:
12
AN:
248906
Hom.:
0
AF XY:
0.0000446
AC XY:
6
AN XY:
134624
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000874
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000471
Gnomad NFE exome
AF:
0.0000711
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000570
AC:
83
AN:
1457382
Hom.:
0
Cov.:
31
AF XY:
0.0000594
AC XY:
43
AN XY:
724306
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000675
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000566
Gnomad4 NFE exome
AF:
0.0000622
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.0000789
AC:
12
AN:
152154
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74328
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000162
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000144
Hom.:
0
Bravo
AF:
0.0000378
ExAC
AF:
0.0000577
AC:
7

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 06, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.412C>T (p.R138C) alteration is located in exon 4 (coding exon 2) of the RITA1 gene. This alteration results from a C to T substitution at nucleotide position 412, causing the arginine (R) at amino acid position 138 to be replaced by a cysteine (C). 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
0.15
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.050
T;T;.
Eigen
Benign
-0.80
Eigen_PC
Benign
-0.78
FATHMM_MKL
Benign
0.32
N
LIST_S2
Benign
0.85
.;D;D
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.053
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.81
L;L;.
PROVEAN
Uncertain
-4.0
D;D;D
REVEL
Benign
0.033
Sift
Uncertain
0.0070
D;D;D
Sift4G
Uncertain
0.013
D;D;D
Polyphen
0.022
B;B;.
Vest4
0.23
MutPred
0.31
Gain of catalytic residue at L140 (P = 0);Gain of catalytic residue at L140 (P = 0);.;
MVP
0.030
MPC
0.28
ClinPred
0.17
T
GERP RS
2.5
Varity_R
0.24
gMVP
0.13

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: rs371991798; hg19: chr12-113629224; COSMIC: COSV55320155; COSMIC: COSV55320155; API