rs527774250

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The ENST00000941486.1(RAF1):c.-430_-429delAG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00347 in 396,792 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Benign (★★★). The gene RAF1 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 2 hom. )

Consequence

RAF1
ENST00000941486.1 5_prime_UTR

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel U:2B:3

Conservation

PhyloP100: 1.61

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: 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:

ENSG00000290072 (HGNC:):

ENSG00000290072 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 -12 ACMG points.

BP6

Variant 3-12664121-ACT-A is Benign according to our data. Variant chr3-12664121-ACT-A is described in ClinVar as Benign. ClinVar VariationId is 40573.Status of the report is reviewed_by_expert_panel, 3 stars.

BS2

High AC in GnomAd4 at 460 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000941486.1. 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.-337_-336delAG	upstream_gene	N/A	NP_002871.1	L7RRS6
RAF1	NM_001354689.3		c.-337_-336delAG	upstream_gene	N/A	NP_001341618.1	A0A0S2Z559
RAF1	NM_001354693.3		c.-337_-336delAG	upstream_gene	N/A	NP_001341622.1	A0A0S2Z4L5

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein
RAF1	ENST00000941486.1	c.-430_-429delAG	5_prime_UTR	Exon 1 of 19	ENSP00000611545.1
RAF1	ENST00000900377.1	c.-430_-429delAG	5_prime_UTR	Exon 1 of 18	ENSP00000570436.1
RAF1	ENST00000941484.1	c.-800_-799delAG	5_prime_UTR	Exon 1 of 18	ENSP00000611543.1

Frequencies

GnomAD3 genomes

AF:

0.00305

AC:

460

AN:

150660

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00184

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00115

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00537

Gnomad OTH

AF:

0.000961

GnomAD4 exome

AF:

0.00373

AC:

917

AN:

246014

Hom.:

AF XY:

0.00364

AC XY:

454

AN XY:

124706

show subpopulations

African (AFR)

AF:

0.00168

AC:

AN:

7164

American (AMR)

AF:

0.00148

AC:

AN:

7428

Ashkenazi Jewish (ASJ)

AF:

0.000759

AC:

AN:

9220

East Asian (EAS)

AF:

0.00

AC:

AN:

22880

South Asian (SAS)

AF:

0.00

AC:

AN:

3022

European-Finnish (FIN)

AF:

0.00178

AC:

AN:

20822

Middle Eastern (MID)

AF:

0.000773

AC:

AN:

1294

European-Non Finnish (NFE)

AF:

0.00516

AC:

815

AN:

157836

Other (OTH)

AF:

0.00208

AC:

AN:

16348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

106

158

211

264

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:

0.00305

AC:

460

AN:

150778

Hom.:

Cov.:

AF XY:

0.00284

AC XY:

209

AN XY:

73604

show subpopulations

African (AFR)

AF:

0.00112

AC:

AN:

40950

American (AMR)

AF:

0.00184

AC:

AN:

15202

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5064

South Asian (SAS)

AF:

0.000209

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.00115

AC:

AN:

10390

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00537

AC:

363

AN:

67616

Other (OTH)

AF:

0.000951

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

117

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:

0.00351

Hom.:

Bravo

AF:

0.00316

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Noonan syndrome (1)

Noonan syndrome with multiple lentigines (1)

not specified (1)

RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.6

Mutation Taster

=288/12

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

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