Genetic Variant RITA1:p.Pro90Ser (chr12-113187014-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_032848.3(RITA1):c.268C>T(p.Pro90Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000274 in 1,607,162 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 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

RITA1
NM_032848.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.60

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]

RITA1 links:

ENSG00000257286 (HGNC:):

ENSG00000257286 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=0.045562565).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RITA1	NM_032848.3 link	c.268C>T	p.Pro90Ser	missense_variant	Exon 3 of 4	ENST00000548278.2	NP_116237.1	Q96K30-1A0A024RBL1
RITA1	NM_001286215.2 link	c.340C>T	p.Pro114Ser	missense_variant	Exon 2 of 3		NP_001273144.1	Q96K30-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RITA1	ENST00000548278.2 link	c.268C>T	p.Pro90Ser	missense_variant	Exon 3 of 4	1	NM_032848.3	ENSP00000449841.1		Q96K30-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000299

AC:

AN:

233772

Hom.:

AF XY:

0.0000315

AC XY:

AN XY:

126942

show subpopulations

Gnomad AFR exome

AF:

0.000275

Gnomad AMR exome

AF:

0.0000609

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:

0.00000957

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000179

AC:

AN:

1454832

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

723118

show subpopulations

Gnomad4 AFR exome

AF:

0.000300

Gnomad4 AMR exome

AF:

0.000138

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:

9.02e-7

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000118

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000409

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:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000291

Hom.:

Bravo

AF:

0.000155

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000495

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.268C>T (p.P90S) alteration is located in exon 3 (coding exon 1) of the RITA1 gene. This alteration results from a C to T substitution at nucleotide position 268, causing the proline (P) at amino acid position 90 to be replaced by a serine (S). 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

0.11

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.012

T;T;.;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.66

.;T;T;T

M_CAP

Benign

0.0049

MetaRNN

Benign

0.046

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;M;.;.

PROVEAN

Uncertain

-2.7

D;D;D;.

REVEL

Benign

0.041

Sift

Benign

0.21

T;T;T;.

Sift4G

Benign

0.31

T;T;T;D

Polyphen

0.035

B;B;.;.

Vest4

0.30

MVP

0.088

MPC

0.34

ClinPred

0.048

GERP RS

2.8

Varity_R

0.11

gMVP

0.22

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