1-155900413-C-A

Variant names:

• chr1-155900413-C-A
• rs764347644
• NM_006912.6:c.635G>T

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.635G>T​(p.Arg212Leu) 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R212W) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RIT1 NM_006912.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.48

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain GTP-binding protein Rit1 (size 218) in uniprot entity RIT1_HUMAN there are 56 pathogenic changes around while only 12 benign (82%) in NM_006912.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1975795).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIT1	NM_006912.6	c.635G>T	p.Arg212Leu	missense_variant	Exon 6 of 6	ENST00000368323.8	NP_008843.1
RIT1	NM_001256821.2	c.686G>T	p.Arg229Leu	missense_variant	Exon 6 of 6		NP_001243750.1
RIT1	NM_001256820.2	c.527G>T	p.Arg176Leu	missense_variant	Exon 5 of 5		NP_001243749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIT1	ENST00000368323.8	c.635G>T	p.Arg212Leu	missense_variant	Exon 6 of 6	1	NM_006912.6	ENSP00000357306.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.0052	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.;.
Eigen	Benign	-0.089
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.012	D;D;D
Sift4G	Uncertain	0.056	T;D;D
Polyphen		0.051	B;.;.
Vest4		0.43
MutPred		0.38		Loss of helix (P = 0.0033);.;.;
MVP		0.47
MPC		1.0
ClinPred		0.59	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.65

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: rs764347644; hg19: chr1-155870204;