3-12663990-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4BA1BP7

This summary comes from the ClinGen Evidence Repository: The c.-204G>C variant in RAF1 is classified as benign because it has been identified in 0.15126% (95% CI of 32/15402) of non-Finnish European chromosomes in gnomAD (BA1; https://gnomad.broadinstitute.org). This variant is not located within the splice consensus sequence and computational splice site prediction tools do not predict an impact on splicing (BP4, BP7). ACMG/AMP Criteria applied: BA1, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA180843/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.0018 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0024 ( 2 hom. )

Consequence

RAF1
NM_002880.4 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:5

Conservation

PhyloP100: 1.43

Publications

1 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.

BP4

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
RAF1	NM_002880.4	MANE Select	c.-204G>C	5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	NP_002871.1
RAF1	NM_002880.4	MANE Select	c.-204G>C	5_prime_UTR	Exon 1 of 17	NP_002871.1
RAF1	NM_001354689.3		c.-204G>C	5_prime_UTR_premature_start_codon_gain	Exon 1 of 18	NP_001341618.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
RAF1	ENST00000251849.9	TSL:1 MANE Select	c.-204G>C	5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	ENSP00000251849.4
RAF1	ENST00000251849.9	TSL:1 MANE Select	c.-204G>C	5_prime_UTR	Exon 1 of 17	ENSP00000251849.4
RAF1	ENST00000442415.7	TSL:5	c.-204G>C	5_prime_UTR_premature_start_codon_gain	Exon 1 of 18	ENSP00000401888.2

Frequencies

GnomAD3 genomes

AF:

0.00181

AC:

276

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000941

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

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:

0.00316

Gnomad OTH

AF:

0.00143

GnomAD4 exome

AF:

0.00238

AC:

586

AN:

246260

Hom.:

Cov.:

AF XY:

0.00254

AC XY:

317

AN XY:

124834

show subpopulations

African (AFR)

AF:

0.000557

AC:

AN:

7176

American (AMR)

AF:

0.00188

AC:

AN:

7434

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9230

East Asian (EAS)

AF:

0.00

AC:

AN:

22894

South Asian (SAS)

AF:

0.00

AC:

AN:

3034

European-Finnish (FIN)

AF:

0.000336

AC:

AN:

20824

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1296

European-Non Finnish (NFE)

AF:

0.00325

AC:

514

AN:

158006

Other (OTH)

AF:

0.00287

AC:

AN:

16366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

124

166

207

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00181

AC:

276

AN:

152322

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.000938

AC:

AN:

41574

American (AMR)

AF:

0.00124

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00316

AC:

215

AN:

68006

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000425

Hom.:

Bravo

AF:

0.00189

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

LEOPARD syndrome 2 (1)

LEOPARD syndrome 2;C1969057:Noonan syndrome 5;C4014656:Dilated cardiomyopathy 1NN (1)

Noonan syndrome 5 (1)

not specified (1)

RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.69

PhyloP100

1.4

PromoterAI

0.049

Neutral

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over