Genetic Variant RITA1:p.Arg138Cys (chr12-113191419-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -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. 13/21 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

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.73

Publications

4 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.052532643).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032848.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RITA1	NM_032848.3	MANE Select	c.412C>T	p.Arg138Cys	missense	Exon 4 of 4	NP_116237.1	Q96K30-1
	RITA1	NM_001286215.2		c.484C>T	p.Arg162Cys	missense	Exon 3 of 3	NP_001273144.1	Q96K30-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RITA1	ENST00000548278.2	TSL:1 MANE Select	c.412C>T	p.Arg138Cys	missense	Exon 4 of 4	ENSP00000449841.1	Q96K30-1
RITA1	ENST00000552495.1	TSL:2	c.484C>T	p.Arg162Cys	missense	Exon 3 of 3	ENSP00000448680.1	Q96K30-3
RITA1	ENST00000549621.5	TSL:2	c.412C>T	p.Arg138Cys	missense	Exon 4 of 4	ENSP00000448289.1	Q96K30-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152154

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000482

AC:

AN:

248906

AF XY:

0.0000446

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 FIN exome

AF:

0.0000471

Gnomad NFE exome

AF:

0.0000711

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000570

AC:

AN:

1457382

Hom.:

Cov.:

AF XY:

0.0000594

AC XY:

AN XY:

724306

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33394

American (AMR)

AF:

0.0000675

AC:

AN:

44460

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26004

East Asian (EAS)

AF:

0.00

AC:

AN:

39594

South Asian (SAS)

AF:

0.00

AC:

AN:

86036

European-Finnish (FIN)

AF:

0.0000566

AC:

AN:

52980

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.0000622

AC:

AN:

1109066

Other (OTH)

AF:

0.000116

AC:

AN:

60100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000144

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000577

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.050

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.85

M_CAP

Benign

0.016

MetaRNN

Benign

0.053

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

PhyloP100

1.7

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.033

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.013

Polyphen

0.022

Vest4

0.23

MutPred

0.31

Gain of catalytic residue at L140 (P = 0)

MVP

0.030

MPC

0.28

ClinPred

0.17

GERP RS

2.5

Varity_R

0.24

gMVP

0.13

Mutation Taster

=86/14

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over