rs869312687

Positions:

• chr1-155910695-T-C
• chr1-155910695-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_006912.6(RIT1):​c.67A>G​(p.Lys23Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K23Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RIT1 NM_006912.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.48

Genes affected

RIT1 (HGNC:10023): (Ras like without CAAX 1) This gene encodes a member of a subfamily of Ras-related GTPases. The encoded protein is involved in regulating p38 MAPK-dependent signaling cascades related to cellular stress. This protein also cooperates with nerve growth factor to promote neuronal development and regeneration. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a chain GTP-binding protein Rit1 (size 218) in uniprot entity RIT1_HUMAN there are 53 pathogenic changes around while only 9 benign (85%) in NM_006912.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155910693-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 581105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922
• PP5: Variant 1-155910695-T-C is Pathogenic according to our data. Variant chr1-155910695-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1695891.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIT1	NM_006912.6	c.67A>G	p.Lys23Glu	missense_variant	2/6	ENST00000368323.8
RIT1	NM_001256821.2	c.118A>G	p.Lys40Glu	missense_variant	2/6
RIT1	NM_001256820.2	c.-2-189A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIT1	ENST00000368323.8	c.67A>G	p.Lys23Glu	missense_variant	2/6	1	NM_006912.6	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Noonan syndrome 8 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.9	H;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.5	D;D;.
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;D;.
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		0.97	D;.;.
Vest4		0.82
MutPred		0.75		Loss of methylation at K23 (P = 0.0045);.;Loss of methylation at K23 (P = 0.0045);
MVP		0.99
MPC		2.2
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.38		Position offset: 5

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: chr1-155880486; COSMIC: COSV64166614; COSMIC: COSV64166614;