NM_002880.4:c.576A>G

Variant names:

• chr3-12608771-T-C
• rs148759910
• NM_002880.4:c.576A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_002880.4(RAF1):​c.576A>G​(p.Gln192Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000275 in 1,613,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene RAF1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: RAF1 NM_002880.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.745
• Publications: 3 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

Specifications for RAF1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 3-12608771-T-C is Benign according to our data. Variant chr3-12608771-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 40597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.745 with no splicing effect.
• BS2: High AC in GnomAd4 at 23 AD gene.

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.576A>G	p.Gln192Gln	synonymous	Exon 5 of 17	NP_002871.1	L7RRS6
	RAF1	NM_001354689.3		c.576A>G	p.Gln192Gln	synonymous	Exon 5 of 18	NP_001341618.1	A0A0S2Z559
	RAF1	NM_001354690.3		c.576A>G	p.Gln192Gln	synonymous	Exon 5 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.576A>G	p.Gln192Gln	synonymous	Exon 5 of 17	ENSP00000251849.4	P04049-1
	RAF1	ENST00000442415.7	TSL:5	c.576A>G	p.Gln192Gln	synonymous	Exon 5 of 18	ENSP00000401888.2	P04049-2
	RAF1	ENST00000900382.1		c.576A>G	p.Gln192Gln	synonymous	Exon 5 of 18	ENSP00000570441.1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152100 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000309

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000155 AC: 39 AN: 251436 AF XY: 0.000162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000281

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000288 AC: 421 AN: 1461756 Hom.: 0 Cov.: 31 AF XY: 0.000283 AC XY: 206 AN XY: 727170

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

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

European-Non Finnish (NFE) AF: 0.000360 AC: 400 AN: 1111902

Other (OTH) AF: 0.000166 AC: 10 AN: 60390

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152100 Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 10 AN XY: 74286

African (AFR) AF: 0.0000242 AC: 1 AN: 41396

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68030

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.000159

EpiCase AF: 0.000763

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)
-	-	1	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	1.8
DANN	Benign	0.38
PhyloP100		-0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs148759910; hg19: chr3-12650270; COSMIC: COSV52581965; COSMIC: COSV52581965;