rs527774250

Variant names:

• chr3-12664121-ACT-A
• rs527774250
• ENST00000491290.2:n.41_42delAG

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The ENST00000491290.2(RAF1):​n.41_42delAG variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00347 in 396,792 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (2 hom.)
• Consequence: RAF1 ENST00000491290.2 non_coding_transcript_exon
• Clinical Significance: Benign reviewed by expert panel U:2 B:3
• Conservation: PhyloP100: 1.61
• Publications: 0 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

ENSG00000290072 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP6: Variant 3-12664121-ACT-A is Benign according to our data. Variant chr3-12664121-ACT-A is described in ClinVar as Benign. ClinVar VariationId is 40573.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High AC in GnomAd4 at 460 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000491290.2. 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.-337_-336delAG		upstream_gene	N/A	NP_002871.1
	RAF1	NM_001354689.3		c.-337_-336delAG		upstream_gene	N/A	NP_001341618.1
	RAF1	NM_001354693.3		c.-337_-336delAG		upstream_gene	N/A	NP_001341622.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAF1	ENST00000491290.2	TSL:4	n.41_42delAG		non_coding_transcript_exon	Exon 1 of 11
	RAF1	ENST00000684903.1		n.-337_-336delAG		non_coding_transcript_exon	Exon 1 of 16	ENSP00000508612.1
	RAF1	ENST00000685348.1		n.-337_-336delAG		non_coding_transcript_exon	Exon 1 of 15	ENSP00000510285.1

Frequencies

GnomAD3 genomes AF: 0.00305 AC: 460 AN: 150660 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00115

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00537

Gnomad OTH AF: 0.000961

GnomAD4 exome AF: 0.00373 AC: 917 AN: 246014 Hom.: 2 AF XY: 0.00364 AC XY: 454 AN XY: 124706

African (AFR) AF: 0.00168 AC: 12 AN: 7164

American (AMR) AF: 0.00148 AC: 11 AN: 7428

Ashkenazi Jewish (ASJ) AF: 0.000759 AC: 7 AN: 9220

East Asian (EAS) AF: 0.00 AC: 0 AN: 22880

South Asian (SAS) AF: 0.00 AC: 0 AN: 3022

European-Finnish (FIN) AF: 0.00178 AC: 37 AN: 20822

Middle Eastern (MID) AF: 0.000773 AC: 1 AN: 1294

European-Non Finnish (NFE) AF: 0.00516 AC: 815 AN: 157836

Other (OTH) AF: 0.00208 AC: 34 AN: 16348

GnomAD4 genome AF: 0.00305 AC: 460 AN: 150778 Hom.: 0 Cov.: 32 AF XY: 0.00284 AC XY: 209 AN XY: 73604

African (AFR) AF: 0.00112 AC: 46 AN: 40950

American (AMR) AF: 0.00184 AC: 28 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5064

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4792

European-Finnish (FIN) AF: 0.00115 AC: 12 AN: 10390

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

European-Non Finnish (NFE) AF: 0.00537 AC: 363 AN: 67616

Other (OTH) AF: 0.000951 AC: 2 AN: 2104

Alfa AF: 0.00351 Hom.: 0

Bravo AF: 0.00316

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	LEOPARD syndrome 2;C1969057:Noonan syndrome 5;C4014656:Dilated cardiomyopathy 1NN (1)
-	1	-	Noonan syndrome (1)
-	1	-	Noonan syndrome with multiple lentigines (1)
-	-	1	not specified (1)
-	-	1	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=288/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs527774250; hg19: chr3-12705620;