rs367785615

chr1-155904721-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006912.6(RIT1):c.237+10C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000296 in 1,596,316 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: RIT1 NM_006912.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.524

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 1-155904721-G-T is Benign according to our data. Variant chr1-155904721-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 477768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000138 (21/152100) while in subpopulation NFE AF= 0.000279 (19/68022). AF 95% confidence interval is 0.000182. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIT1	NM_006912.6	c.237+10C>A		intron_variant		ENST00000368323.8
RIT1	NM_001256820.2	c.129+10C>A		intron_variant
RIT1	NM_001256821.2	c.288+10C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIT1	ENST00000368323.8	c.237+10C>A		intron_variant		1	NM_006912.6	P3

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000338 AC: 85 AN: 251288 Hom.: 1 AF XY: 0.000317 AC XY: 43 AN XY: 135836

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.000721

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000313 AC: 452 AN: 1444216 Hom.: 1 Cov.: 28 AF XY: 0.000304 AC XY: 219 AN XY: 719692

Gnomad4 AFR exome AF: 0.0000302

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: 0.000432

Gnomad4 NFE exome AF: 0.000369

Gnomad4 OTH exome AF: 0.000385

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152100 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74290

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000255 Hom.: 0

Bravo AF: 0.000181

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 8 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 08, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 04, 2017

Variant summary: The RIT1 c.237+10C>A variant involves the alteration of a non-conserved intronic nucleotide. Mutation taster predicts a benign outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 64/121326 control chromosomes (1 homozygote) from ExAC, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.00093 (62/66676). This frequency is about 74 times the estimated maximal expected allele frequency of a pathogenic RIT1 variant (0.0000125), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Taken together, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	20
Dann	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs367785615; hg19: chr1-155874512;