rs727504451

Variant names:

• chr3-12599669-AAAGGGAGGGCCCC-A
• rs727504451
• NM_002880.4:c.1108+9_1108+21delGGGGCCCTCCCTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BA1 BP7 BP5

This summary comes from the ClinGen Evidence Repository: The c.1108+9_1108+21del variant is located in intron 10 of the RAF1 gene. This variant has a filtering allele frequency of 0.05951% in the European (non-Finnish) population in gnomAD v2, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1 and therefore meets this criterion (BA1). The variant is a synonymous (silent) variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). Additionally, this variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM internal data; GTR Lab ID's: 26957, 21766; ClinVar SCV000205113.4, SCV000209007.2). 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, BP5, BP7. (Specification Version 2.3, 12/3/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA182757/MONDO:0021060/040

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (2 hom.)
• Consequence: RAF1 NM_002880.4 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:8
• Conservation: PhyloP100: 1.84
• 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: 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 -10 ACMG points.

• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: 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.1108+9_1108+21delGGGGCCCTCCCTT		intron	N/A	NP_002871.1	L7RRS6
	RAF1	NM_001354689.3		c.1168+9_1168+21delGGGGCCCTCCCTT		intron	N/A	NP_001341618.1	A0A0S2Z559
	RAF1	NM_001354690.3		c.1108+9_1108+21delGGGGCCCTCCCTT		intron	N/A	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.1108+9_1108+21delGGGGCCCTCCCTT		intron	N/A	ENSP00000251849.4	P04049-1
	RAF1	ENST00000442415.7	TSL:5	c.1168+9_1168+21delGGGGCCCTCCCTT		intron	N/A	ENSP00000401888.2	P04049-2
	RAF1	ENST00000900382.1		c.1168+9_1168+21delGGGGCCCTCCCTT		intron	N/A	ENSP00000570441.1

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000720

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000358 AC: 90 AN: 251410 AF XY: 0.000346

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000721

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000677 AC: 975 AN: 1440108 Hom.: 2 AF XY: 0.000623 AC XY: 447 AN XY: 717922

African (AFR) AF: 0.0000908 AC: 3 AN: 33050

American (AMR) AF: 0.0000671 AC: 3 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26006

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.00 AC: 0 AN: 85762

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.000856 AC: 935 AN: 1092216

Other (OTH) AF: 0.000520 AC: 31 AN: 59658

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74338

African (AFR) AF: 0.000169 AC: 7 AN: 41436

American (AMR) AF: 0.000262 AC: 4 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.000720 AC: 49 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.000391 Hom.: 0

Bravo AF: 0.000329

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	3	RASopathy (3)
-	-	1	Noonan syndrome (1)
-	1	-	Noonan syndrome and Noonan-related syndrome (1)
-	-	1	RAF1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs727504451; hg19: chr3-12641168;