12-113191657-C-G

Variant names:

• chr12-113191657-C-G
• NM_032848.3:c.650C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032848.3(RITA1):​c.650C>G​(p.Ala217Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RITA1 NM_032848.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.25

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 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=0.051568985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RITA1	NM_032848.3	c.650C>G	p.Ala217Gly	missense_variant	Exon 4 of 4	ENST00000548278.2	NP_116237.1
RITA1	NM_001286215.2	c.722C>G	p.Ala241Gly	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.650C>G	p.Ala217Gly	missense_variant	Exon 4 of 4	1	NM_032848.3	ENSP00000449841.1
RITA1	ENST00000552495.1	c.722C>G	p.Ala241Gly	missense_variant	Exon 3 of 3	2		ENSP00000448680.1
RITA1	ENST00000549621.5	c.650C>G	p.Ala217Gly	missense_variant	Exon 4 of 4	2		ENSP00000448289.1
ENSG00000257286	ENST00000552525.1	n.69+436G>C		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461800 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.650C>G (p.A217G) alteration is located in exon 4 (coding exon 2) of the RITA1 gene. This alteration results from a C to G substitution at nucleotide position 650, causing the alanine (A) at amino acid position 217 to be replaced by a glycine (G). 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	0.086
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.9
DANN	Benign	0.64
DEOGEN2	Benign	0.0059	T;T;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.52	.;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.052	T;T;T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.0040
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.45	T;T;T
Polyphen		0.39	B;B;.
Vest4		0.096
MutPred		0.16		Gain of catalytic residue at P213 (P = 0.0134);Gain of catalytic residue at P213 (P = 0.0134);.;
MVP		0.030
MPC		0.21
ClinPred		0.077	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.047
gMVP		0.061

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: chr12-113629462;