3-12608923-C-T

Variant names:

• chr3-12608923-C-T
• rs1553614748
• NM_002880.4:c.424G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_002880.4(RAF1):​c.424G>A​(p.Ala142Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A142S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAF1 NM_002880.4 missense, splice_region
• Scores: Splicing: ADA: 0.9966
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.90
• 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), 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_002880.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAF1	NM_002880.4	c.424G>A	p.Ala142Thr	missense_variant, splice_region_variant	Exon 5 of 17	ENST00000251849.9	NP_002871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAF1	ENST00000251849.9	c.424G>A	p.Ala142Thr	missense_variant, splice_region_variant	Exon 5 of 17	1	NM_002880.4	ENSP00000251849.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	0.29	N;N;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.45	N;N;N
REVEL	Uncertain	0.54
Sift	Benign	0.034	D;D;D
Sift4G	Uncertain	0.036	D;D;D
Polyphen		0.15	B;.;.
Vest4		0.53
MutPred		0.45		Loss of catalytic residue at A142 (P = 0.0407);Loss of catalytic residue at A142 (P = 0.0407);.;
MVP		0.79
MPC		0.56
ClinPred		0.80	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.55
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.82
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: rs1553614748; hg19: chr3-12650422;