1-155900398-G-A

Variant names:

• chr1-155900398-G-A
• NM_006912.6:c.650C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_006912.6(RIT1):​c.650C>T​(p.Ser217Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S217S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RIT1 NM_006912.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.83

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 3 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=0.3791616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIT1	NM_006912.6	c.650C>T	p.Ser217Leu	missense_variant	Exon 6 of 6	ENST00000368323.8	NP_008843.1
RIT1	NM_001256821.2	c.701C>T	p.Ser234Leu	missense_variant	Exon 6 of 6		NP_001243750.1
RIT1	NM_001256820.2	c.542C>T	p.Ser181Leu	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.650C>T	p.Ser217Leu	missense_variant	Exon 6 of 6	1	NM_006912.6	ENSP00000357306.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460770 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726784

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;.
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.55	N;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.011	D;T;D
Polyphen		0.60	P;.;.
Vest4		0.58
MutPred		0.29		Loss of phosphorylation at S217 (P = 0.0031);.;.;
MVP		0.75
MPC		0.78
ClinPred		0.72	D
GERP RS		5.1
Varity_R		0.27
gMVP		0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-155870189;