rs5746226

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002880.4(RAF1):c.991-42T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0126 in 1,466,904 control chromosomes in the GnomAD database, including 168 homozygotes. 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 0.0095 ( 13 hom., cov: 32)

Exomes 𝑓: 0.013 ( 155 hom. )

Consequence

RAF1
NM_002880.4 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.59

Publications

2 publications found

Variant links:

COSMIC-nc: COSV52577292

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

RAF1 links:

Genome browser will be placed here

ACMG classification

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

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 3-12599850-A-G is Benign according to our data. Variant chr3-12599850-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 258855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 1441 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RAF1	NM_002880.4	MANE Select	c.991-42T>C	intron	N/A	NP_002871.1	L7RRS6
RAF1	NM_001354689.3		c.1051-42T>C	intron	N/A	NP_001341618.1	A0A0S2Z559
RAF1	NM_001354690.3		c.991-42T>C	intron	N/A	NP_001341619.1	P04049-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RAF1	ENST00000251849.9	TSL:1 MANE Select	c.991-42T>C	intron	N/A	ENSP00000251849.4	P04049-1
RAF1	ENST00000442415.7	TSL:5	c.1051-42T>C	intron	N/A	ENSP00000401888.2	P04049-2
RAF1	ENST00000900382.1		c.1051-42T>C	intron	N/A	ENSP00000570441.1

Frequencies

GnomAD3 genomes

AF:

0.00949

AC:

1444

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00256

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0124

Gnomad ASJ

AF:

0.0337

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0112

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0135

Gnomad OTH

AF:

0.0186

GnomAD2 exomes

AF:

0.0114

AC:

2863

AN:

251074

AF XY:

0.0117

show subpopulations

Gnomad AFR exome

AF:

0.00216

Gnomad AMR exome

AF:

0.0101

Gnomad ASJ exome

AF:

0.0339

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00249

Gnomad NFE exome

AF:

0.0142

Gnomad OTH exome

AF:

0.0154

GnomAD4 exome

AF:

0.0130

AC:

17024

AN:

1314586

Hom.:

155

Cov.:

AF XY:

0.0130

AC XY:

8630

AN XY:

662044

show subpopulations

African (AFR)

AF:

0.00196

AC:

AN:

30610

American (AMR)

AF:

0.0106

AC:

474

AN:

44524

Ashkenazi Jewish (ASJ)

AF:

0.0321

AC:

809

AN:

25186

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39020

South Asian (SAS)

AF:

0.0121

AC:

1009

AN:

83322

European-Finnish (FIN)

AF:

0.00262

AC:

140

AN:

53346

Middle Eastern (MID)

AF:

0.0145

AC:

AN:

5508

European-Non Finnish (NFE)

AF:

0.0141

AC:

13737

AN:

977492

Other (OTH)

AF:

0.0128

AC:

714

AN:

55578

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

890

1780

2669

3559

4449

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

484

968

1452

1936

2420

<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:

0.00946

AC:

1441

AN:

152318

Hom.:

Cov.:

AF XY:

0.00886

AC XY:

660

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00255

AC:

106

AN:

41566

American (AMR)

AF:

0.0124

AC:

190

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0337

AC:

117

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.0112

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00170

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0135

AC:

916

AN:

68026

Other (OTH)

AF:

0.0184

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

151

227

302

378

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0132

Hom.:

Bravo

AF:

0.00991

Asia WGS

AF:

0.00751

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

3.8

(source)

DANN

Benign

0.41

PhyloP100

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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