rs1051208

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000251849.9(RAF1):​c.*266C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 514,178 control chromosomes in the GnomAD database, including 7,571 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3033 hom., cov: 32)
Exomes 𝑓: 0.15 ( 4538 hom. )

Consequence

RAF1
ENST00000251849.9 3_prime_UTR

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.312
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]
MKRN2 (HGNC:7113): (makorin ring finger protein 2) This gene encodes a probable E3 ubiquitin ligase containing several zinc finger domains, that is a member of the makorin RING zinc-finger protein family. This gene overlaps the v-raf-1 murine leukemia viral oncogene homolog 1 (RAF1) gene in an antisense orientation and may have a co-regulatory function with RAF1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
Variant 3-12584248-G-A is Benign according to our data. Variant chr3-12584248-G-A is described in ClinVar as [Benign]. Clinvar id is 40631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RAF1NM_002880.4 linkuse as main transcriptc.*266C>T 3_prime_UTR_variant 17/17 ENST00000251849.9 NP_002871.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RAF1ENST00000251849.9 linkuse as main transcriptc.*266C>T 3_prime_UTR_variant 17/171 NM_002880.4 ENSP00000251849 P3P04049-1

Frequencies

GnomAD3 genomes
AF:
0.188
AC:
28560
AN:
152036
Hom.:
3021
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.255
Gnomad AMI
AF:
0.336
Gnomad AMR
AF:
0.269
Gnomad ASJ
AF:
0.148
Gnomad EAS
AF:
0.0268
Gnomad SAS
AF:
0.107
Gnomad FIN
AF:
0.141
Gnomad MID
AF:
0.104
Gnomad NFE
AF:
0.155
Gnomad OTH
AF:
0.186
GnomAD4 exome
AF:
0.146
AC:
52839
AN:
362024
Hom.:
4538
Cov.:
4
AF XY:
0.141
AC XY:
26761
AN XY:
189364
show subpopulations
Gnomad4 AFR exome
AF:
0.250
Gnomad4 AMR exome
AF:
0.319
Gnomad4 ASJ exome
AF:
0.142
Gnomad4 EAS exome
AF:
0.0297
Gnomad4 SAS exome
AF:
0.101
Gnomad4 FIN exome
AF:
0.148
Gnomad4 NFE exome
AF:
0.150
Gnomad4 OTH exome
AF:
0.150
GnomAD4 genome
AF:
0.188
AC:
28607
AN:
152154
Hom.:
3033
Cov.:
32
AF XY:
0.186
AC XY:
13833
AN XY:
74380
show subpopulations
Gnomad4 AFR
AF:
0.255
Gnomad4 AMR
AF:
0.269
Gnomad4 ASJ
AF:
0.148
Gnomad4 EAS
AF:
0.0269
Gnomad4 SAS
AF:
0.106
Gnomad4 FIN
AF:
0.141
Gnomad4 NFE
AF:
0.155
Gnomad4 OTH
AF:
0.189
Alfa
AF:
0.151
Hom.:
620
Bravo
AF:
0.204
Asia WGS
AF:
0.115
AC:
400
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
LEOPARD syndrome 2 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Noonan syndrome 5 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.85
CADD
Benign
2.4
DANN
Benign
0.33
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1051208; hg19: chr3-12625747; COSMIC: COSV50109978; COSMIC: COSV50109978; API