3-12604200-G-C

Variant names:

• chr3-12604200-G-C
• rs80338796
• NM_002880.4:c.770C>G
• RAF1 p.Ser257Trp

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+6 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 6 classification points (ACMG Germline Pathogenicity v2019). PM1PM2_SupportingPM5PP3

The NM_002880.4(RAF1):c.770C>G (p.Ser257Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000186 (AC=3) in the gnomAD database across 1,614,050 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000116. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 10.00). Variant has been reported in ClinVar as Uncertain Significance (no review stars). A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.S257T: Likely_pathogenic (ClinVar VariationId 618340, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S257= (synonymous): Likely_benign (ClinVar VariationId 1112676, 1 star) This exact variant is established as oncogenic in: CGI (Cancer Genome Interpreter). The variant position is a cancer hotspot (cancerhotspots.org): 25 samples carry this exact amino acid change out of 50 samples with a variant at this residue. This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Noonan syndrome 5 (ns5); it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RAF1 NM_002880.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 B:1
• Conservation: PhyloP100: 10.0
• Publications: 1 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

Classification according to ACMG Germline Pathogenicity v2019

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: Likely_pathogenic. The variant received 6 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 31 pathogenic, 0 benign (OR vs. background: 315.0).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000116 — borderline rare for AD/XL gene (threshold 0.0001) — PM2 supporting.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.S257T: Likely_pathogenic (ClinVar VariationId 618340, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.S257= (synonymous): Likely_benign (ClinVar VariationId 1112676, 1 star)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_002880.4. 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.770C>G p.Ser257Trp	missense	Exon 7 of 17	Prot: NP_002871.1 UniProt:
	RAF1 NM_001354689.3		c.770C>G p.Ser257Trp	missense	Exon 7 of 18	Prot: NP_001341618.1 UniProt:
	RAF1 NM_001354690.3		c.770C>G p.Ser257Trp	missense	Exon 7 of 17	Prot: NP_001341619.1 UniProt:

RAF1 NM_002880.4

MANE Select

HGVSc / HGVSpc.770C>Gp.Ser257Trp

Exon rankExon 7 of 17

missense

Prot: NP_002871.1UniProt: L7RRS6P04049-1

RAF1 NM_001354689.3

HGVSc / HGVSpc.770C>Gp.Ser257Trp

Exon rankExon 7 of 18

missense

Prot: NP_001341618.1UniProt: P04049-2A0A0S2Z559

RAF1 NM_001354690.3

HGVSc / HGVSpc.770C>Gp.Ser257Trp

Exon rankExon 7 of 17

missense

Prot: NP_001341619.1UniProt: L7RRS6P04049-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RAF1 ENST00000251849.9	TSL:1MANE Select	c.770C>G p.Ser257Trp	missense	Exon 7 of 17	Prot: ENSP00000251849.4 UniProt:
	RAF1 ENST00000442415.7	TSL:5	c.770C>G p.Ser257Trp	missense	Exon 7 of 18	Prot: ENSP00000401888.2 UniProt:
	RAF1 ENST00000900382.1		c.770C>G p.Ser257Trp	missense	Exon 7 of 18	Prot: ENSP00000570441.1 UniProt:

RAF1 ENST00000251849.9

TSL:1MANE Select

HGVSc / HGVSpc.770C>Gp.Ser257Trp

Exon rankExon 7 of 17

missense

Prot: ENSP00000251849.4UniProt: P04049-1

RAF1 ENST00000442415.7

TSL:5

HGVSc / HGVSpc.770C>Gp.Ser257Trp

Exon rankExon 7 of 18

missense

Prot: ENSP00000401888.2UniProt: P04049-2

RAF1 ENST00000900382.1

HGVSc / HGVSpc.770C>Gp.Ser257Trp

Exon rankExon 7 of 18

missense

Prot: ENSP00000570441.1UniProt: P04049-2

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000131	AC:2	Hom:0	AN:152170	Cov:33
GnomAD2 exomes	AF: 0.00000398	AC:1	Hom:	AN:251462	Cov:
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461880	Cov:31
GnomAD4 genome	AF: 0.0000131	AC:2	Hom:0	AN:152170	Cov:33
TOPMed (Bravo)	AF: 0.0000151	AC:4	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:207520	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000172	1	58232	0.0000124	1	80510

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

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	-	1	LEOPARD syndrome 2;C1969057:Noonan syndrome 5 (1)
1	-	-	Noonan syndrome 5 (1)
1	-	-	RASopathy (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	30
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.94	D
FuncVEP CTI	Pathogenic	0.94
GPN-Star LLR	N/A	-11
GPN-Star score	N/A	11
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.39	D
Mutation Taster	N/A	0/100	disease causing
MutationAssessor	Pathogenic	3.0	M
PhyloP100	Pathogenic	10
popEVE	Uncertain	-5.0
PrimateAI	Pathogenic	0.83	D
PromoterAI	N/A	-0.013	Neutral
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.93
VESM-3B	Benign	-15

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 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: rs80338796;

hg19: chr3-12645699;

COSMIC: COSV52579821;

COSMIC: COSV52579821;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar