12-113191500-C-T

Variant names:

• chr12-113191500-C-T
• NM_032848.3:c.493C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032848.3(RITA1):​c.493C>T​(p.His165Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RITA1 NM_032848.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06

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]

ENSG00000257286 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2940533).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RITA1	NM_032848.3	c.493C>T	p.His165Tyr	missense_variant	Exon 4 of 4	ENST00000548278.2	NP_116237.1
RITA1	NM_001286215.2	c.565C>T	p.His189Tyr	missense_variant	Exon 3 of 3		NP_001273144.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RITA1	ENST00000548278.2	c.493C>T	p.His165Tyr	missense_variant	Exon 4 of 4	1	NM_032848.3	ENSP00000449841.1
RITA1	ENST00000552495.1	c.565C>T	p.His189Tyr	missense_variant	Exon 3 of 3	2		ENSP00000448680.1
RITA1	ENST00000549621.5	c.493C>T	p.His165Tyr	missense_variant	Exon 4 of 4	2		ENSP00000448289.1
ENSG00000257286	ENST00000552525.1	n.69+593G>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.493C>T (p.H165Y) 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 493, causing the histidine (H) at amino acid position 165 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	Benign	0.20
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.080	T;T;.
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.77	.;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.4	M;M;.
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Benign	0.17
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.050	T;T;D
Polyphen		1.0	D;D;.
Vest4		0.44
MutPred		0.20		Gain of catalytic residue at G168 (P = 0.0014);Gain of catalytic residue at G168 (P = 0.0014);.;
MVP		0.27
MPC		0.83
ClinPred		0.97	D
GERP RS		4.6
Varity_R		0.30
gMVP		0.34

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-113629305;