1-155900444-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_006912.6(RIT1):c.604A>T(p.Ser202Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RIT1 NM_006912.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.61

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 Uncertain_significance. Variant got 2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.23878428).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIT1	NM_006912.6	c.604A>T	p.Ser202Cys	missense_variant	6/6	ENST00000368323.8
RIT1	NM_001256821.2	c.655A>T	p.Ser219Cys	missense_variant	6/6
RIT1	NM_001256820.2	c.496A>T	p.Ser166Cys	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIT1	ENST00000368323.8	c.604A>T	p.Ser202Cys	missense_variant	6/6	1	NM_006912.6	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727240

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 13, 2015

The p.Ser219Cys variant in RIT1 has been identified by our laboratory in 1 fetus with a cystic hygroma and hydrops, which was inherited from a parent of unknown clinical status. It was not observed in large population studies. Computational prediction tools and conservation analyses suggest that the p.Ser219Cyc variant may impact the protein, though this information is not predictive enough to det ermine pathogenicity. In summary, the clinical significance of the p.Ser219Cys v ariant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.27	T;.;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.90	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.045	D;T;D
Sift4G	Uncertain	0.027	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.38
MutPred		0.28		Loss of phosphorylation at S202 (P = 0.0166);.;.;
MVP		0.68
MPC		0.78
ClinPred		0.72	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.80

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: rs876657981; hg19: chr1-155870235;