ENST00000941486.1:c.-430_-429delAG

Variant names:

• chr3-12664121-ACT-A
• rs527774250
• ENST00000941486.1:c.-430_-429delAG

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACGS-UK Somatic Oncogenicity v2025).

The ENST00000941486.1(RAF1):c.-430_-429delAG variant causes a 5 prime UTR change. Note: ENST00000941486.1 is not a MANE Select or MANE Plus Clinical transcript for RAF1; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The gene RAF1 is a known oncogene (CancerMine: 1 TSG, 57 oncogene, 3 driver citations). The variant allele was found at a cumulative frequency of 0.00347 (AC=1,377) in the gnomAD database across 396,792 control chromosomes, including 2 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.00491. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (2 hom.)
• Consequence: RAF1 ENST00000941486.1 5_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:3
• Conservation: PhyloP100: 1.61
• Publications: 0 publications found

Genes affected

RAF1 (HGNC:9829): (Raf-1 proto-oncogene, serine/threonine kinase) This gene is the cellular homolog of viral raf gene (v-raf). The encoded protein is a MAP kinase kinase kinase (MAP3K), which functions downstream of the Ras family of membrane associated GTPases to which it binds directly. Once activated, the cellular RAF1 protein can phosphorylate to activate the dual specificity protein kinases MEK1 and MEK2, which in turn phosphorylate to activate the serine/threonine specific protein kinases, ERK1 and ERK2. Activated ERKs are pleiotropic effectors of cell physiology and play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation and cell migration. Mutations in this gene are associated with Noonan syndrome 5 and LEOPARD syndrome 2. [provided by RefSeq, Jul 2008]

RAF1 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Noonan syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics
• dilated cardiomyopathy 1NN

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• LEOPARD syndrome 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen
• cardiofaciocutaneous syndrome

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000290072 (HGNC:):

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for RAF1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
No applied criteria Uncheck "Show applied only" above to review all 20 criteria.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: ENST00000941486.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RAF1 NM_002880.4	MANE Select	c.-337_-336delAG	upstream_gene	N/A	Prot: NP_002871.1 UniProt:
	RAF1 NM_001354689.3		c.-337_-336delAG	upstream_gene	N/A	Prot: NP_001341618.1 UniProt:
	RAF1 NM_001354693.3		c.-337_-336delAG	upstream_gene	N/A	Prot: NP_001341622.1 UniProt:

RAF1 NM_002880.4

MANE Select

HGVSc / HGVSpc.-337_-336delAG

Exon rankN/A

upstream_gene

Prot: NP_002871.1UniProt: L7RRS6P04049-1

RAF1 NM_001354689.3

HGVSc / HGVSpc.-337_-336delAG

Exon rankN/A

upstream_gene

Prot: NP_001341618.1UniProt: P04049-2A0A0S2Z559

RAF1 NM_001354693.3

HGVSc / HGVSpc.-337_-336delAG

Exon rankN/A

upstream_gene

Prot: NP_001341622.1UniProt: A0A0S2Z4L5A0ACI8T5E0

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RAF1 ENST00000941486.1		c.-430_-429delAG	5_prime_UTR	Exon 1 of 19	Prot: ENSP00000611545.1 UniProt:
	RAF1 ENST00000900377.1		c.-430_-429delAG	5_prime_UTR	Exon 1 of 18	Prot: ENSP00000570436.1 UniProt:
	RAF1 ENST00000941484.1		c.-800_-799delAG	5_prime_UTR	Exon 1 of 18	Prot: ENSP00000611543.1 UniProt:

RAF1 ENST00000941486.1

HGVSc / HGVSpc.-430_-429delAG

Exon rankExon 1 of 19

5_prime_UTR

Prot: ENSP00000611545.1UniProt: P04049-2

RAF1 ENST00000900377.1

HGVSc / HGVSpc.-430_-429delAG

Exon rankExon 1 of 18

5_prime_UTR

Prot: ENSP00000570436.1UniProt: P04049-1

RAF1 ENST00000941484.1

HGVSc / HGVSpc.-800_-799delAG

Exon rankExon 1 of 18

5_prime_UTR

Prot: ENSP00000611543.1UniProt: P04049-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00305	AC:460	Hom:0	AN:150660	Cov:32
GnomAD4 exome	AF: 0.00373	AC:917	Hom:2	AN:246014	Cov:
GnomAD4 genome	AF: 0.00305	AC:460	Hom:0	AN:150778	Cov:32
TOPMed (Bravo)	AF: 0.00316	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00348	AC:85	Hom:0	AN:24450	Cov:
Local & regional cohorts 4 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.00128	AC:3	Hom:0	AN:2342	Cov:
Denmark Genome	AF: 0.0133	AC:4	Hom:	AN:300	Cov:
Turkish Variome	AF: 0.00259	AC:4	Hom:0	AN:1546	Cov:
UK10K	AF: 0.00383	AC:29	Hom:	AN:7562	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.000971	82	84452	0.00114	128	112238

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	LEOPARD syndrome 2;C1969057:Noonan syndrome 5;C4014656:Dilated cardiomyopathy 1NN (1)
-	-	1	not specified (1)
-	-	1	RASopathy (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	288/12	polymorphism
PhyloP100	Benign	1.6

Showing 2 of 2 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
SpliceAI score (max)	Benign	0.030	Details are displayed if max score is > 0.2

Showing 1 of 1 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs527774250;

hg19: chr3-12705620;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar