3-12604202-C-A

Variant names:

• chr3-12604202-C-A
• rs397516826
• NM_002880.4:c.768G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2_Supporting PS4_Moderate PS3_Supporting PM1

This summary comes from the ClinGen Evidence Repository: The c.768G>T variant in the RAF1 gene is a missense variant predicted to cause substitution of arginine by serine at amino acid 256 (p.Arg256Ser). This variant is absent from gnomAD v2 (PM2_Supporting). The computational predictor REVEL gives a score of 0.665, which does not meet PP3 or BP4. This variant is located in the CR2 critical functional domain as defined by the ClinGen RASopathy Expert Panel (PM1). This variant has been reported in 3 individuals with clinical features of Noonan syndrome (PS4_Moderate, PMIDs: 17603483, 22190897, 31292302). In vitro functional studies provide some evidence that the p.Arg256Ser variant may impact protein function (PMID:20679480). ERK phosphorylation assay showed that the p.Arg256Ser variant led to significantly increased phosphorylation compared to wild-type (PS3_Supporting; PMID:20679480). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathies based on ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS4_Moderate, PM1, PS3_Supporting, PM2_Supporting (Specification Version 2.3, 12/3/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA261625/MONDO:0021060/040

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAF1 NM_001354689.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: -0.0880
• Publications: 16 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), Ambry Genetics, PanelApp Australia, G2P
• dilated cardiomyopathy 1NN

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

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354689.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAF1	NM_002880.4	MANE Select	c.768G>T	p.Arg256Ser	missense	Exon 7 of 17	NP_002871.1
	RAF1	NM_001354689.3		c.768G>T	p.Arg256Ser	missense	Exon 7 of 18	NP_001341618.1
	RAF1	NM_001354690.3		c.768G>T	p.Arg256Ser	missense	Exon 7 of 17	NP_001341619.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAF1	ENST00000251849.9	TSL:1 MANE Select	c.768G>T	p.Arg256Ser	missense	Exon 7 of 17	ENSP00000251849.4
	RAF1	ENST00000442415.7	TSL:5	c.768G>T	p.Arg256Ser	missense	Exon 7 of 18	ENSP00000401888.2
	RAF1	ENST00000900382.1		c.768G>T	p.Arg256Ser	missense	Exon 7 of 18	ENSP00000570441.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	RASopathy (3)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Noonan syndrome (1)
1	-	-	Noonan syndrome 5 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.29	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		-0.088
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.54		Gain of glycosylation at S252 (P = 0.0093)
MVP		0.98
MPC		1.4
ClinPred		0.97	D
GERP RS		2.5
PromoterAI		-0.035	Neutral
Varity_R		0.84
gMVP		0.82
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs397516826; hg19: chr3-12645701;