1-155907238-T-C

Variant names:

• chr1-155907238-T-C
• rs12037177
• NM_006912.6:c.164-2434A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006912.6(RIT1):​c.164-2434A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 147,908 control chromosomes in the GnomAD database, including 6,795 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.28 (6795 hom., cov: 29)
• Consequence: RIT1 NM_006912.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.474
• Publications: 12 publications found

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]

RIT1 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 8

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006912.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIT1	NM_006912.6	MANE Select	c.164-2434A>G		intron	N/A	NP_008843.1	Q92963-1
	RIT1	NM_001256821.2		c.215-2434A>G		intron	N/A	NP_001243750.1	Q92963-3
	RIT1	NM_001256820.2		c.56-2434A>G		intron	N/A	NP_001243749.1	Q92963-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIT1	ENST00000368323.8	TSL:1 MANE Select	c.164-2434A>G		intron	N/A	ENSP00000357306.3	Q92963-1
	RIT1	ENST00000609492.1	TSL:1	c.164-2434A>G		intron	N/A	ENSP00000476612.1	V9GYC3
	RIT1	ENST00000368322.7	TSL:3	c.215-2434A>G		intron	N/A	ENSP00000357305.3	Q92963-3

Frequencies

GnomAD3 genomes AF: 0.284 AC: 41921 AN: 147828 Hom.: 6785 Cov.: 29

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.751

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.192

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.289

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.284 AC: 41938 AN: 147908 Hom.: 6795 Cov.: 29 AF XY: 0.286 AC XY: 20531 AN XY: 71734

African (AFR) AF: 0.285 AC: 11468 AN: 40204

American (AMR) AF: 0.326 AC: 4732 AN: 14534

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 786 AN: 3456

East Asian (EAS) AF: 0.751 AC: 3768 AN: 5018

South Asian (SAS) AF: 0.306 AC: 1454 AN: 4756

European-Finnish (FIN) AF: 0.220 AC: 2042 AN: 9290

Middle Eastern (MID) AF: 0.198 AC: 57 AN: 288

European-Non Finnish (NFE) AF: 0.250 AC: 16880 AN: 67390

Other (OTH) AF: 0.285 AC: 588 AN: 2064

Alfa AF: 0.192 Hom.: 586

Bravo AF: 0.300

Asia WGS AF: 0.459 AC: 1475 AN: 3214

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	8.0
DANN	Benign	0.70
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12037177; hg19: chr1-155877029;