3-12599851-A-G

Variant names:

• chr3-12599851-A-G
• rs5746225
• NM_002880.4:c.991-43T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002880.4(RAF1):​c.991-43T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0126 in 1,464,626 control chromosomes in the GnomAD database, including 166 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0095 (13 hom., cov: 32)
  • Exomes 𝑓: 0.013 (153 hom.)
• Consequence: RAF1 NM_002880.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0340
• Publications: 3 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-12599851-A-G is Benign according to our data. Variant chr3-12599851-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 258856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1440 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAF1	NM_002880.4	MANE Select	c.991-43T>C		intron	N/A	NP_002871.1
	RAF1	NM_001354689.3		c.1051-43T>C		intron	N/A	NP_001341618.1
	RAF1	NM_001354690.3		c.991-43T>C		intron	N/A	NP_001341619.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAF1	ENST00000251849.9	TSL:1 MANE Select	c.991-43T>C		intron	N/A	ENSP00000251849.4
	RAF1	ENST00000686409.1		n.1999T>C		non_coding_transcript_exon	Exon 7 of 11
	RAF1	ENST00000692069.1		n.1514T>C		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.00948 AC: 1443 AN: 152202 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.0337

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.0114 AC: 2865 AN: 251058 AF XY: 0.0117

Gnomad AFR exome AF: 0.00216

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.0340

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00250

Gnomad NFE exome AF: 0.0142

Gnomad OTH exome AF: 0.0154

GnomAD4 exome AF: 0.0130 AC: 17035 AN: 1312306 Hom.: 153 Cov.: 20 AF XY: 0.0131 AC XY: 8636 AN XY: 661066

African (AFR) AF: 0.00196 AC: 60 AN: 30566

American (AMR) AF: 0.0106 AC: 474 AN: 44522

Ashkenazi Jewish (ASJ) AF: 0.0321 AC: 808 AN: 25174

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 38996

South Asian (SAS) AF: 0.0122 AC: 1014 AN: 83304

European-Finnish (FIN) AF: 0.00262 AC: 140 AN: 53348

Middle Eastern (MID) AF: 0.0146 AC: 80 AN: 5488

European-Non Finnish (NFE) AF: 0.0141 AC: 13742 AN: 975378

Other (OTH) AF: 0.0129 AC: 716 AN: 55530

GnomAD4 genome AF: 0.00945 AC: 1440 AN: 152320 Hom.: 13 Cov.: 32 AF XY: 0.00885 AC XY: 659 AN XY: 74480

African (AFR) AF: 0.00253 AC: 105 AN: 41584

American (AMR) AF: 0.0124 AC: 190 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0337 AC: 117 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.0112 AC: 54 AN: 4822

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0135 AC: 916 AN: 68030

Other (OTH) AF: 0.0185 AC: 39 AN: 2112

Alfa AF: 0.0131 Hom.: 6

Bravo AF: 0.00991

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.97
DANN	Benign	0.46
PhyloP100		-0.034
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs5746225; hg19: chr3-12641350; COSMIC: COSV52577301;