1-155900444-T-G

Variant names:

• chr1-155900444-T-G
• rs876657981
• NM_006912.6:c.604A>C

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>C​(p.Ser202Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. S202C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RIT1 NM_006912.6 missense
• Clinical Significance: Not reported in ClinVar
• 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 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=0.22781762).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIT1	NM_006912.6	c.604A>C	p.Ser202Arg	missense_variant	Exon 6 of 6	ENST00000368323.8	NP_008843.1
RIT1	NM_001256821.2	c.655A>C	p.Ser219Arg	missense_variant	Exon 6 of 6		NP_001243750.1
RIT1	NM_001256820.2	c.496A>C	p.Ser166Arg	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.604A>C	p.Ser202Arg	missense_variant	Exon 6 of 6	1	NM_006912.6	ENSP00000357306.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.;.
Eigen	Benign	0.080
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	T;D;T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.90	L;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.033	D;D;D
Sift4G	Uncertain	0.051	T;T;D
Polyphen		0.73	P;.;.
Vest4		0.38
MutPred		0.26		Loss of phosphorylation at S202 (P = 0.0166);.;.;
MVP		0.71
MPC		1.3
ClinPred		0.78	D
GERP RS		5.1
Varity_R		0.16
gMVP		0.81

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;