dbSNP rs2290161: RAF1:c.1193+39T>C (chr3-12591669-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002880.4(RAF1):c.1193+39T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,557,200 control chromosomes in the GnomAD database, including 213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene RAF1 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.015 ( 32 hom., cov: 32)

Exomes 𝑓: 0.014 ( 181 hom. )

Consequence

RAF1
NM_002880.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.948

Publications

5 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: ClinGen, Orphanet
Noonan syndrome 5
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
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: 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: Orphanet, ClinGen
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

new If you want to explore the variant's impact on the transcript NM_002880.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 3-12591669-A-G is Benign according to our data. Variant chr3-12591669-A-G is described in ClinVar as Benign. ClinVar VariationId is 258851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0146 (2228/152288) while in subpopulation AMR AF = 0.0445 (680/15294). AF 95% confidence interval is 0.0417. There are 32 homozygotes in GnomAd4. There are 1153 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2228 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.1193+39T>C	intron	N/A	NP_002871.1	L7RRS6
RAF1	NM_001354689.3		c.1253+39T>C	intron	N/A	NP_001341618.1	A0A0S2Z559
RAF1	NM_001354690.3		c.1193+39T>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.1193+39T>C	intron	N/A	ENSP00000251849.4	P04049-1
RAF1	ENST00000494557.2	TSL:1	n.1004+39T>C	intron	N/A
RAF1	ENST00000442415.7	TSL:5	c.1253+39T>C	intron	N/A	ENSP00000401888.2	P04049-2

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2218

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00582

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0445

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.0229

Gnomad SAS

AF:

0.0182

Gnomad FIN

AF:

0.0106

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0133

Gnomad OTH

AF:

0.0278

GnomAD2 exomes

AF:

0.0170

AC:

4274

AN:

250920

AF XY:

0.0164

show subpopulations

Gnomad AFR exome

AF:

0.00480

Gnomad AMR exome

AF:

0.0369

Gnomad ASJ exome

AF:

0.00398

Gnomad EAS exome

AF:

0.0277

Gnomad FIN exome

AF:

0.00950

Gnomad NFE exome

AF:

0.0137

Gnomad OTH exome

AF:

0.0191

GnomAD4 exome

AF:

0.0136

AC:

19070

AN:

1404912

Hom.:

181

Cov.:

AF XY:

0.0134

AC XY:

9405

AN XY:

702318

show subpopulations

African (AFR)

AF:

0.00543

AC:

175

AN:

32252

American (AMR)

AF:

0.0388

AC:

1731

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.00337

AC:

AN:

25790

East Asian (EAS)

AF:

0.0261

AC:

1031

AN:

39444

South Asian (SAS)

AF:

0.0157

AC:

1332

AN:

85072

European-Finnish (FIN)

AF:

0.0102

AC:

545

AN:

53392

Middle Eastern (MID)

AF:

0.0111

AC:

AN:

5676

European-Non Finnish (NFE)

AF:

0.0125

AC:

13280

AN:

1060186

Other (OTH)

AF:

0.0141

AC:

826

AN:

58470

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

963

1926

2889

3852

4815

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

538

1076

1614

2152

2690

<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:

0.0146

AC:

2228

AN:

152288

Hom.:

Cov.:

AF XY:

0.0155

AC XY:

1153

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00582

AC:

242

AN:

41562

American (AMR)

AF:

0.0445

AC:

680

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

3466

East Asian (EAS)

AF:

0.0230

AC:

119

AN:

5180

South Asian (SAS)

AF:

0.0180

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0106

AC:

113

AN:

10624

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0133

AC:

907

AN:

68020

Other (OTH)

AF:

0.0318

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

116

233

349

466

582

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0129

Hom.:

Bravo

AF:

0.0165

Asia WGS

AF:

0.0510

AC:

178

AN:

3478

ClinVar

ClinVar submissions

Significance: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

-0.91

CADD

Benign

0.34

(source)

DANN

Benign

0.25

PhyloP100

-0.95

PromoterAI

-0.0066

Neutral

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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