rs192632236

Variant names:

• chr3-12618603-C-T
• rs192632236
• NM_002880.4:c.119G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-12618603-C-T
• chr3-12618603-C-A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BA1 BP4 BS2_Supporting BP5 BS4

This summary comes from the ClinGen Evidence Repository: The c.119G>A variant in the RAF1 gene is a missense variant predicted to cause substitution of arginine by histidine at amino acid 40 (p.Arg40His). The filtering allele frequency of this variant is 0.5265% for Admixed American chromosomes in gnomAD v4, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). The computational predictor REVEL gives a score of 0.281, which is below the threshold of 0.3 and does not predict a damaging effect on RAF1 function (BP4). This variant has been identified in a patient with an alternate molecular basis for disease and did not segregate with disease in affected family members (BP5, BS4; GeneDx internal data; GTR ID: 26957; SCV000171283.11). Additionally this variant was identified in multiple healthy individuals (BS2_P, Eurofins, SCV000227278.5; Illumina, SCV000440638.3; Ambry Genetics, SCV000736788.4). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BS4, BS2_supporting, BP4, BP5 (Specification Version 2.1, 9/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA201617/MONDO:0021060/040

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: RAF1 NM_002880.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:10
• Conservation: PhyloP100: 5.77
• Publications: 7 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: Benign. The variant received -15 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BS4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.119G>A	p.Arg40His	missense	Exon 2 of 17	NP_002871.1	L7RRS6
	RAF1	NM_001354689.3		c.119G>A	p.Arg40His	missense	Exon 2 of 18	NP_001341618.1	A0A0S2Z559
	RAF1	NM_001354690.3		c.119G>A	p.Arg40His	missense	Exon 2 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.119G>A	p.Arg40His	missense	Exon 2 of 17	ENSP00000251849.4	P04049-1
	RAF1	ENST00000442415.7	TSL:5	c.119G>A	p.Arg40His	missense	Exon 2 of 18	ENSP00000401888.2	P04049-2
	RAF1	ENST00000900382.1		c.119G>A	p.Arg40His	missense	Exon 2 of 18	ENSP00000570441.1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00118 AC: 298 AN: 251486 AF XY: 0.000765

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00850

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000228 AC: 334 AN: 1461894 Hom.: 2 Cov.: 32 AF XY: 0.000157 AC XY: 114 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00722 AC: 323 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112012

Other (OTH) AF: 0.0000993 AC: 6 AN: 60396

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74446

African (AFR) AF: 0.00 AC: 0 AN: 41544

American (AMR) AF: 0.00150 AC: 23 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000133 Hom.: 1

Bravo AF: 0.000620

ExAC AF: 0.000931 AC: 113

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	2	RASopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	LEOPARD syndrome 2 (1)
-	1	-	Noonan syndrome 1 (1)
-	-	1	Noonan syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.28
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.33	T
Polyphen		0.33	B
Vest4		0.66
MVP		0.95
MPC		0.58
ClinPred		0.046	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.61
Mutation Taster		=206/94	polymorphism

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: rs192632236; hg19: chr3-12660102;