rs5746223

Positions:

• chr3-12599926-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.30

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAF1	NM_002880.4	c.991-118A>G		intron_variant		ENST00000251849.9	NP_002871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAF1	ENST00000251849.9	c.991-118A>G		intron_variant		1	NM_002880.4	ENSP00000251849.4

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21414 AN: 152118 Hom.: 1764 Cov.: 32

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

Gnomad4 AFR exome AF: 0.234

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.119

Gnomad4 EAS exome AF: 0.0323

Gnomad4 SAS exome AF: 0.0753

Gnomad4 FIN exome AF: 0.146

Gnomad4 NFE exome AF: 0.106

Gnomad4 OTH exome AF: 0.113

GnomAD4 genome AF: 0.141 AC: 21422 AN: 152236 Hom.: 1767 Cov.: 32 AF XY: 0.140 AC XY: 10456 AN XY: 74434

Gnomad4 AFR AF: 0.223

Gnomad4 AMR AF: 0.130

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.0247

Gnomad4 SAS AF: 0.0735

Gnomad4 FIN AF: 0.153

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.119

Alfa AF: 0.130 Hom.: 186

Bravo AF: 0.144

Asia WGS AF: 0.0720 AC: 253 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.34
DANN	Benign	0.72
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

Other links and lift over

dbSNP: rs5746223; hg19: chr3-12641425;