rs527774250

Variant names:

• chr3-12664121-ACT-A
• rs527774250
• ENST00000941486.1:c.-430_-429delAG

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BS2BP6_Very_Strong

The ENST00000941486.1(RAF1):c.-430_-429delAG variant causes a 5 prime UTR change. Note: ENST00000941486.1 is not a MANE Select or MANE Plus Clinical transcript for RAF1; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.00347 (AC=1,377) in the gnomAD database across 396,792 control chromosomes, including 2 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.00491. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (2 hom.)
• Consequence: RAF1 ENST00000941486.1 5_prime_UTR
• Clinical Significance: Benign reviewed by expert panel 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), PanelApp Australia, G2P, Ambry Genetics
• dilated cardiomyopathy 1NN

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• LEOPARD syndrome 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
• 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:):

Classification according to ACMG Germline Pathogenicity v2019

Specifications for RAF1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP6: ClinVar ≥3 stars benign — very strong (BP6); ClinVar germline classification: Benign/Likely Benign, 3 star(s).
• BS2: ≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 2.; Very high cumulative gnomAD AC = 1377 (any gene).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: ENST00000941486.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	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	L7RRS6
	RAF1	NM_001354689.3		c.-337_-336delAG		upstream_gene	N/A	NP_001341618.1	P04049-2
	RAF1	NM_001354693.3		c.-337_-336delAG		upstream_gene	N/A	NP_001341622.1	A0A0S2Z4L5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAF1	ENST00000941486.1		c.-430_-429delAG		5_prime_UTR	Exon 1 of 19	ENSP00000611545.1	P04049-2
	RAF1	ENST00000900377.1		c.-430_-429delAG		5_prime_UTR	Exon 1 of 18	ENSP00000570436.1	P04049-1
	RAF1	ENST00000941484.1		c.-800_-799delAG		5_prime_UTR	Exon 1 of 18	ENSP00000611543.1	P04049-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	0.00305	460	0	150660	32
GnomAD4 exome	0.00373	917	2	246014
GnomAD4 genome	0.00305	460	0	150778	32
TOPMed (Bravo)	0.00316
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	0.00348	85	0	24450
Local & regional cohorts 4 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	0.00128	3	0	2342
Denmark Genome	0.0133	4		300
Turkish Variome	0.00259	4	0	1546
UK10K	0.00383	29		7562

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.000971	82	84452	0.00114	128	112238

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

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	not specified (1)
-	-	1	RASopathy (1)

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
Mutation Taster	N/A	polymorphism	288/12
PhyloP100	Benign	-	1.6

Showing 2 of 2 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.030

Showing 1 of 1 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs527774250;

hg19: chr3-12705620;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar