1-155900625-G-A

Variant names:

• chr1-155900625-G-A
• rs1749409
• NM_006912.6:c.430-7C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006912.6(RIT1):​c.430-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.902 in 1,613,008 control chromosomes in the GnomAD database, including 662,209 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (52278 hom., cov: 32)
  • Exomes 𝑓: 0.91 (609931 hom.)
• Consequence: RIT1 NM_006912.6 splice_region, intron
• Scores: Splicing: ADA: 0.00001202
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.987
• Publications: 25 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-155900625-G-A is Benign according to our data. Variant chr1-155900625-G-A is described in ClinVar as Benign. ClinVar VariationId is 181519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.918 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.430-7C>T		splice_region intron	N/A	NP_008843.1	Q92963-1
	RIT1	NM_001256821.2		c.481-7C>T		splice_region intron	N/A	NP_001243750.1	Q92963-3
	RIT1	NM_001256820.2		c.322-7C>T		splice_region 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.430-7C>T		splice_region intron	N/A	ENSP00000357306.3	Q92963-1
	RIT1	ENST00000609492.1	TSL:1	c.430-7C>T		splice_region intron	N/A	ENSP00000476612.1	V9GYC3
	RIT1	ENST00000368322.7	TSL:3	c.481-7C>T		splice_region intron	N/A	ENSP00000357305.3	Q92963-3

Frequencies

GnomAD3 genomes AF: 0.812 AC: 123461 AN: 152038 Hom.: 52266 Cov.: 32

Gnomad AFR AF: 0.543

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.907

Gnomad ASJ AF: 0.875

Gnomad EAS AF: 0.939

Gnomad SAS AF: 0.865

Gnomad FIN AF: 0.890

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.925

Gnomad OTH AF: 0.844

GnomAD2 exomes AF: 0.886 AC: 222070 AN: 250514 AF XY: 0.889

Gnomad AFR exome AF: 0.533

Gnomad AMR exome AF: 0.945

Gnomad ASJ exome AF: 0.874

Gnomad EAS exome AF: 0.940

Gnomad FIN exome AF: 0.888

Gnomad NFE exome AF: 0.920

Gnomad OTH exome AF: 0.890

GnomAD4 exome AF: 0.911 AC: 1331394 AN: 1460852 Hom.: 609931 Cov.: 37 AF XY: 0.910 AC XY: 661582 AN XY: 726698

African (AFR) AF: 0.528 AC: 17631 AN: 33386

American (AMR) AF: 0.941 AC: 41981 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.877 AC: 22916 AN: 26116

East Asian (EAS) AF: 0.945 AC: 37504 AN: 39698

South Asian (SAS) AF: 0.856 AC: 73715 AN: 86098

European-Finnish (FIN) AF: 0.894 AC: 47756 AN: 53412

Middle Eastern (MID) AF: 0.830 AC: 4780 AN: 5762

European-Non Finnish (NFE) AF: 0.928 AC: 1031310 AN: 1111392

Other (OTH) AF: 0.891 AC: 53801 AN: 60354

GnomAD4 genome AF: 0.812 AC: 123492 AN: 152156 Hom.: 52278 Cov.: 32 AF XY: 0.813 AC XY: 60483 AN XY: 74392

African (AFR) AF: 0.542 AC: 22482 AN: 41442

American (AMR) AF: 0.907 AC: 13859 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.875 AC: 3038 AN: 3472

East Asian (EAS) AF: 0.939 AC: 4877 AN: 5194

South Asian (SAS) AF: 0.866 AC: 4180 AN: 4828

European-Finnish (FIN) AF: 0.890 AC: 9421 AN: 10588

Middle Eastern (MID) AF: 0.816 AC: 240 AN: 294

European-Non Finnish (NFE) AF: 0.925 AC: 62900 AN: 68034

Other (OTH) AF: 0.844 AC: 1785 AN: 2114

Alfa AF: 0.890 Hom.: 255506

Bravo AF: 0.802

Asia WGS AF: 0.875 AC: 3043 AN: 3478

EpiCase AF: 0.918

EpiControl AF: 0.921

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Noonan syndrome 8 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.5
DANN	Benign	0.52
PhyloP100		0.99
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs1749409; hg19: chr1-155870416;