chr1-155904739-C-A

Position:

• chr1-155904739-C-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The ENST00000368323.8(RIT1):​c.229G>T​(p.Ala77Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,670 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A77G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RIT1 ENST00000368323.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.89

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 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000368323.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155904738-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 850519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874
• PP5: Variant 1-155904739-C-A is Pathogenic according to our data. Variant chr1-155904739-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 561621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIT1	NM_006912.6	c.229G>T	p.Ala77Ser	missense_variant	4/6	ENST00000368323.8	NP_008843.1
RIT1	NM_001256821.2	c.280G>T	p.Ala94Ser	missense_variant	4/6		NP_001243750.1
RIT1	NM_001256820.2	c.121G>T	p.Ala41Ser	missense_variant	3/5		NP_001243749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIT1	ENST00000368323.8	c.229G>T	p.Ala77Ser	missense_variant	4/6	1	NM_006912.6	ENSP00000357306	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457670 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725490

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 8 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 17, 2021	This sequence change replaces alanine with serine at codon 77 of the RIT1 protein (p.Ala77Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala77 amino acid residue in RIT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26714497, 26757980, 27101134, 29402968). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RIT1 protein function. ClinVar contains an entry for this variant (Variation ID: 561621). This missense change has been observed in individuals with clinical features of Noonan syndrome (PMID: 26714497; Invitae). This variant is not present in population databases (ExAC no frequency). -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same or different nucleotide change resulting in same amino acid change has been previously reported to be associated with RIT1 related disorder (ClinVar ID: VCV000561621, PMID:26714497). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 26714497). Different missense change at the same codon have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000183403, VCV000228289, VCV000850519, PMID:25049390, 26714497). It is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.809>=0.6, 3CNET: 0.994>=0.75). Missense changes are a common disease-causing mechanism. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Noonan syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics, Centre for Human Genetics

-

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 13, 2019

Published functional studies demonstrate a damaging effect; A77S confers a gain-of-function by causing significant increase in Elk1 activation in comparison to wild-type (Yaoita et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26714497, 27109146, 29734338, 24469055) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;.;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.6	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.9	D;D;D;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.82
MutPred		0.67		Gain of relative solvent accessibility (P = 0.0082);.;.;Gain of relative solvent accessibility (P = 0.0082);
MVP		0.79
MPC		1.8
ClinPred		0.97	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.86
gMVP		0.86

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

Other links and lift over

dbSNP: rs869025191; hg19: chr1-155874530; COSMIC: COSV64171290;