rs670523

Variant names:

• chr1-155908941-A-G
• rs670523
• NM_006912.6:c.163+1509T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-155908941-A-G
• chr1-155908941-A-T

Variant summary

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

The NM_006912.6(RIT1):​c.163+1509T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.48 in 151,870 control chromosomes in the GnomAD database, including 21,993 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 0.48 (21993 hom., cov: 29)
• Consequence: RIT1 NM_006912.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.771
• Publications: 60 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: Orphanet, ClinGen
• Noonan syndrome 8

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.662 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.163+1509T>C		intron	N/A	NP_008843.1	Q92963-1
	RIT1	NM_001256821.2		c.214+1509T>C		intron	N/A	NP_001243750.1	Q92963-3
	RIT1	NM_001256820.2		c.55+1509T>C		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.163+1509T>C		intron	N/A	ENSP00000357306.3	Q92963-1
	RIT1	ENST00000609492.1	TSL:1	c.163+1509T>C		intron	N/A	ENSP00000476612.1	V9GYC3
	RIT1	ENST00000368322.7	TSL:3	c.214+1509T>C		intron	N/A	ENSP00000357305.3	Q92963-3

Frequencies

GnomAD3 genomes AF: 0.480 AC: 72885 AN: 151752 Hom.: 21992 Cov.: 29

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.599

Gnomad AMR AF: 0.567

Gnomad ASJ AF: 0.647

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.540

Gnomad FIN AF: 0.620

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.667

Gnomad OTH AF: 0.522

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

GnomAD4 genome AF: 0.480 AC: 72878 AN: 151870 Hom.: 21993 Cov.: 29 AF XY: 0.478 AC XY: 35504 AN XY: 74206

African (AFR) AF: 0.118 AC: 4911 AN: 41444

American (AMR) AF: 0.566 AC: 8614 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.647 AC: 2246 AN: 3470

East Asian (EAS) AF: 0.161 AC: 832 AN: 5152

South Asian (SAS) AF: 0.541 AC: 2601 AN: 4812

European-Finnish (FIN) AF: 0.620 AC: 6516 AN: 10510

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.667 AC: 45323 AN: 67948

Other (OTH) AF: 0.527 AC: 1114 AN: 2112

Alfa AF: 0.568 Hom.: 44863

Bravo AF: 0.455

Asia WGS AF: 0.335 AC: 1164 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.8
DANN	Benign	0.49
PhyloP100		0.77
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: rs670523; hg19: chr1-155878732;