18-43115446-A-G

Position:

• chr18-43115446-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002930.4(RIT2):​c.74T>C​(p.Met25Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RIT2 NM_002930.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.87

Genes affected

RIT2 (HGNC:10017): (Ras like without CAAX 2) RIN belongs to the RAS (HRAS; MIM 190020) superfamily of small GTPases (Shao et al., 1999 [PubMed 10545207]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIT2	NM_002930.4	c.74T>C	p.Met25Thr	missense_variant	1/5	ENST00000326695.10	NP_002921.1
RIT2	NM_001272077.2	c.74T>C	p.Met25Thr	missense_variant	1/6		NP_001259006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIT2	ENST00000326695.10	c.74T>C	p.Met25Thr	missense_variant	1/5	1	NM_002930.4	ENSP00000321805	P1
RIT2	ENST00000589109.5	c.74T>C	p.Met25Thr	missense_variant	1/6	1		ENSP00000467217
RIT2	ENST00000590910.1	c.74T>C	p.Met25Thr	missense_variant	1/6	5		ENSP00000466620
RIT2	ENST00000650392.1	c.74T>C	p.Met25Thr	missense_variant, NMD_transcript_variant	1/7			ENSP00000497708

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460066 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726362

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Ambry Genetics

Sep 01, 2021

The c.74T>C (p.M25T) alteration is located in exon 1 (coding exon 1) of the RIT2 gene. This alteration results from a T to C substitution at nucleotide position 74, causing the methionine (M) at amino acid position 25 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;.;D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.8	L;L;.
MutationTaster	Benign	0.96	D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.0	N;.;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D;.;.
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.93	P;P;.
Vest4		0.81
MutPred		0.72		Gain of glycosylation at M25 (P = 0.0426);Gain of glycosylation at M25 (P = 0.0426);Gain of glycosylation at M25 (P = 0.0426);
MVP		0.87
MPC		1.5
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.64
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-40695411;