1-155904365-G-T

Variant names:

• chr1-155904365-G-T
• NM_006912.6:c.375C>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.375C>A​(p.Asp125Glu) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D125G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RIT1 NM_006912.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.215

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=0.10841495).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIT1	NM_006912.6	c.375C>A	p.Asp125Glu	missense_variant	Exon 5 of 6	ENST00000368323.8	NP_008843.1
RIT1	NM_001256821.2	c.426C>A	p.Asp142Glu	missense_variant	Exon 5 of 6		NP_001243750.1
RIT1	NM_001256820.2	c.267C>A	p.Asp89Glu	missense_variant	Exon 4 of 5		NP_001243749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIT1	ENST00000368323.8	c.375C>A	p.Asp125Glu	missense_variant	Exon 5 of 6	1	NM_006912.6	ENSP00000357306.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

RIT1-related disorder Uncertain:1

Jan 09, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RIT1 c.426C>A variant is predicted to result in the amino acid substitution p.Asp142Glu. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Uncertain	0.97
DEOGEN2	Benign	0.33	T;.;.;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.78
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.74	T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.69	N;N;N;.
REVEL	Benign	0.16
Sift	Benign	0.44	T;T;T;.
Sift4G	Benign	0.45	T;T;T;.
Polyphen		0.0010	B;.;.;.
Vest4		0.38
MutPred		0.55		Gain of MoRF binding (P = 0.1198);.;.;Gain of MoRF binding (P = 0.1198);
MVP		0.45
MPC		0.73
ClinPred		0.17	T
GERP RS		-0.39
Varity_R		0.13
gMVP		0.63

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: chr1-155874156;