rs5746223

Variant names:

• chr3-12599926-T-C
• rs5746223
• NM_002880.4:c.991-118A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 publications found

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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, G2P
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAF1	NM_002880.4	c.991-118A>G		intron_variant	Intron 9 of 16	ENST00000251849.9	NP_002871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAF1	ENST00000251849.9	c.991-118A>G		intron_variant	Intron 9 of 16	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

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

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

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: 29 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7209 AN: 68020

Other (OTH) AF: 0.119 AC: 252 AN: 2110

Alfa AF: 0.134 Hom.: 208

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.34
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)

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

Other links and lift over

dbSNP: rs5746223; hg19: chr3-12641425;