rs727504451

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BA1BP7BP5

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

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel U:1B:7

Conservation

PhyloP100: 1.84

Publications

0 publications found

Variant links:

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

RAF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAF1	NM_002880.4 link	c.1108+9_1108+21delGGGGCCCTCCCTT		intron_variant	Intron 10 of 16	ENST00000251849.9	NP_002871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAF1	ENST00000251849.9 link	c.1108+9_1108+21delGGGGCCCTCCCTT		intron_variant	Intron 10 of 16	1	NM_002880.4	ENSP00000251849.4

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

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:

AN:

251410

AF XY:

0.000346

show subpopulations

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.:

AF XY:

0.000623

AC XY:

447

AN XY:

717922

show subpopulations

African (AFR)

AF:

0.0000908

AC:

AN:

33050

American (AMR)

AF:

0.0000671

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26006

East Asian (EAS)

AF:

0.00

AC:

AN:

39576

South Asian (SAS)

AF:

0.00

AC:

AN:

85762

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.000856

AC:

935

AN:

1092216

Other (OTH)

AF:

0.000520

AC:

AN:

59658

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

119

159

199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000394

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41436

American (AMR)

AF:

0.000262

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000720

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000391

Hom.:

Bravo

AF:

0.000329

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

RASopathy

Benign:3

Dec 03, 2024

ClinGen RASopathy Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

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) -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 07, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is found in NOONAN panel(s). -

not specified

Benign:2

Mar 31, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.1108+9_1108+21del in intron 10 of RAF1: This variant is not expected to have c linical significance because it does not alter an amino acid residue, is not loc ated within the splice consensus sequence, and splice prediction models do not s uggest an impact to splicing. -

Aug 05, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RAF1 c.1108+9_1108+21del13 alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00036 in 251410 control chromosomes, predominantly at a frequency of 0.00072 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 28.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAF1 causing Noonan Syndrome And Related Conditions phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign, including a benign classification by ClinGen RASopathy Variant Curation Expert Panel. Based on the evidence outlined above, the variant was classified as benign. -

Noonan syndrome and Noonan-related syndrome

Uncertain:1

May 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Noonan syndrome

Benign:1

Sep 22, 2020

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1168+9_1168+21del splice region variant has a frequency of 0.0003465 (98 of 282,788 alleles) in gnomAD v2.1.1 with a maximum allele frequency of 0.0006814 (88 of 129,138) in the European non-Finnish population (http://gnomad.broadinstitute.org). This 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). This variant is not predicted to impact splicing (BP7). This variant has been classified as benign by the ClinGen RASopathy Variant Curation Expert Panel with additional unpublished patient data (SCV000616427.3). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria, as specified by the ClinGen RASopathy Variant Curation Expert Panel (PMID:29493581): BA1, BP7. -

RAF1-related disorder

Benign:1

Jul 08, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.8

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over