rs730881012

chr1-155910878-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The ENST00000609492.1(RIT1):c.-117G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000479 in 1,585,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: RIT1 ENST00000609492.1 5_prime_UTR
• Scores: Splicing: ADA: 0.00004223
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0850

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07235709).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000502 (72/1433334) while in subpopulation MID AF= 0.000523 (3/5740). AF 95% confidence interval is 0.000321. There are 0 homozygotes in gnomad4_exome. There are 38 alleles in male gnomad4_exome subpopulation. Median coverage is 39. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIT1	NM_006912.6	c.-43-74G>A		intron_variant		ENST00000368323.8
RIT1	NM_001256821.2	c.8G>A	p.Arg3Lys	missense_variant, splice_region_variant	1/6
RIT1	NM_001256820.2	c.-3+365G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIT1	ENST00000368323.8	c.-43-74G>A		intron_variant		1	NM_006912.6	P3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000132 AC: 26 AN: 196632 Hom.: 0 AF XY: 0.000169 AC XY: 18 AN XY: 106350

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000542

Gnomad ASJ exome AF: 0.000110

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000606

Gnomad OTH exome AF: 0.000383

GnomAD4 exome AF: 0.0000502 AC: 72 AN: 1433334 Hom.: 0 Cov.: 39 AF XY: 0.0000534 AC XY: 38 AN XY: 711006

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000489

Gnomad4 ASJ exome AF: 0.0000390

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000954

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000337

Gnomad4 OTH exome AF: 0.0000673

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74366

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000604

ExAC AF: 0.0000933 AC: 11

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

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 26, 2016

The p.Arg3Lys variant in RIT1 has not been previously reported in individuals wi th Noonan spectrum disorders, but has been identified in 8/49232 chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 730881012). This variant is located in the last base of the exon, which is part of the 5? splice region. Computational tools do not suggest an impact to splicin g or an impact to the protein. However, this information is not predictive enoug h to rule out pathogenicity. In summary, the clinical significance of the p.Arg3 Lys variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	9.1
Dann	Benign	0.91
Eigen	Benign	0.055
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.0080
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.11
MutPred		0.36		Gain of methylation at R3 (P = 0.0063);
MVP		0.44
MPC		0.79
ClinPred		0.043	T
GERP RS		-1.3
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000042
dbscSNV1_RF	Benign	0.062
SpliceAI score (max)		0.010		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: rs730881012; hg19: chr1-155880669;