rs3730271

Variant names:

• chr3-12604195-A-C
• rs3730271
• NM_002880.4:c.775T>G

Your query was ambiguous. Multiple possible variants found:

• chr3-12604195-A-C
• chr3-12604195-A-G
• chr3-12604195-A-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP2 PS2 PM2 PM5_Strong PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The c.775T>G (p.Ser259Ala) variant in RAF1 was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). It has been reported as a confirmed de novo occurrence in 2 probands (PS2_VeryStrong; SCV000808501.1). The variant has been identified in 1 proband with Noonan syndrome (PS4_Supporting; SCV000710868.2). At least 2 other pathogenic missense variants have been previously identified at the Ser259 codon of RAF1 which may indicate that this residue is critical to the function of the protein (PM5_Strong; ClinVar 40601, 44633). A functional assay has been performed on c.775T>G (p.Ser259Ala), but given that it is not currently an approved assay outlined by the RASopathy VCEP, it has not been assessed for PS3 at this time (PMID:23391722). Finally, the variant is located in RAF1, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID:29493581). Of note, this variant has also been observed in association with somatic malignancies; however, analysis and classification of somatic variation is currently not used to inform germline classifications for the RASopathies. In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS4_Supporting, PM5_Strong, PM2, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA351512423/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 33)
• Consequence: RAF1 NM_002880.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 9.32
• Publications: 62 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• dilated cardiomyopathy 1NN

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

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

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

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

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

  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: Pathogenic. The variant received 12 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002880.4. 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
	RAF1	NM_002880.4	MANE Select	c.775T>G	p.Ser259Ala	missense	Exon 7 of 17	NP_002871.1	L7RRS6
	RAF1	NM_001354689.3		c.775T>G	p.Ser259Ala	missense	Exon 7 of 18	NP_001341618.1	A0A0S2Z559
	RAF1	NM_001354690.3		c.775T>G	p.Ser259Ala	missense	Exon 7 of 17	NP_001341619.1	P04049-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAF1	ENST00000251849.9	TSL:1 MANE Select	c.775T>G	p.Ser259Ala	missense	Exon 7 of 17	ENSP00000251849.4	P04049-1
	RAF1	ENST00000442415.7	TSL:5	c.775T>G	p.Ser259Ala	missense	Exon 7 of 18	ENSP00000401888.2	P04049-2
	RAF1	ENST00000900382.1		c.775T>G	p.Ser259Ala	missense	Exon 7 of 18	ENSP00000570441.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
-	1	-	not specified (1)
1	-	-	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		9.3
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.94	P
Vest4		0.66
MutPred		0.44		Gain of glycosylation at S257 (P = 0.0137)
MVP		0.83
MPC		0.73
ClinPred		0.93	D
GERP RS		5.7
PromoterAI		-0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.67
Mutation Taster		=10/90	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: rs3730271; hg19: chr3-12645694; COSMIC: COSV52586258;