NM_002880.4:c.991-118A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002880.4(RAF1):c.991-118A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,180,058 control chromosomes in the GnomAD database, including 8,221 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1767 hom., cov: 32)

Exomes 𝑓: 0.11 ( 6454 hom. )

Consequence

RAF1
NM_002880.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -4.30

Publications

6 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: 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

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 3-12599926-T-C is Benign according to our data. Variant chr3-12599926-T-C is described in ClinVar as Benign. ClinVar VariationId is 1265091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

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.991-118A>G	intron	N/A	NP_002871.1	L7RRS6
RAF1	NM_001354689.3		c.1051-118A>G	intron	N/A	NP_001341618.1	A0A0S2Z559
RAF1	NM_001354690.3		c.991-118A>G	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.991-118A>G	intron	N/A	ENSP00000251849.4	P04049-1
RAF1	ENST00000442415.7	TSL:5	c.1051-118A>G	intron	N/A	ENSP00000401888.2	P04049-2
RAF1	ENST00000900382.1		c.1051-118A>G	intron	N/A	ENSP00000570441.1

Frequencies

GnomAD3 genomes

AF:

0.141

AC:

21414

AN:

152118

Hom.:

1764

Cov.:

show subpopulations

Gnomad AFR

AF:

0.223

Gnomad AMI

AF:

0.218

Gnomad AMR

AF:

0.131

Gnomad ASJ

AF:

0.109

Gnomad EAS

AF:

0.0250

Gnomad SAS

AF:

0.0744

Gnomad FIN

AF:

0.153

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.106

Gnomad OTH

AF:

0.121

GnomAD4 exome

AF:

0.107

AC:

109611

AN:

1027822

Hom.:

6454

AF XY:

0.105

AC XY:

55668

AN XY:

528548

show subpopulations

African (AFR)

AF:

0.234

AC:

5761

AN:

24616

American (AMR)

AF:

0.108

AC:

4651

AN:

42898

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

2778

AN:

23348

East Asian (EAS)

AF:

0.0323

AC:

1212

AN:

37520

South Asian (SAS)

AF:

0.0753

AC:

5754

AN:

76376

European-Finnish (FIN)

AF:

0.146

AC:

7495

AN:

51290

Middle Eastern (MID)

AF:

0.129

AC:

452

AN:

3510

European-Non Finnish (NFE)

AF:

0.106

AC:

76316

AN:

722426

Other (OTH)

AF:

0.113

AC:

5192

AN:

45838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

5343

10685

16028

21370

26713

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2266

4532

6798

9064

11330

<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:

0.141

AC:

21422

AN:

152236

Hom.:

1767

Cov.:

AF XY:

0.140

AC XY:

10456

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.223

AC:

9266

AN:

41536

American (AMR)

AF:

0.130

AC:

1990

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.109

AC:

379

AN:

3470

East Asian (EAS)

AF:

0.0247

AC:

128

AN:

5188

South Asian (SAS)

AF:

0.0735

AC:

355

AN:

4832

European-Finnish (FIN)

AF:

0.153

AC:

1615

AN:

10584

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.106

AC:

7209

AN:

68020

Other (OTH)

AF:

0.119

AC:

252

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

892

1784

2675

3567

4459

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

222

444

666

888

1110

<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:

0.134

Hom.:

208

Bravo

AF:

0.144

Asia WGS

AF:

0.0720

AC:

253

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.34

(source)

DANN

Benign

0.72

PhyloP100

-4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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