rs527774250

chr3-12664121-ACT-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000688543.1(RAF1):c.-337_-336del variant causes a 5 prime UTR 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 ENST00000688543.1 5_prime_UTR
• Clinical Significance: Benign reviewed by expert panel U:2 B:3
• Conservation: PhyloP100: 1.61

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]

ACMG classification

Verdict is Benign. Variant got -16 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 id is 40573.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00305 (460/150778) while in subpopulation NFE AF= 0.00537 (363/67616). AF 95% confidence interval is 0.00491. There are 0 homozygotes in gnomad4. There are 209 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 460 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAF1	NM_002880.4			upstream_gene_variant		ENST00000251849.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAF1	ENST00000251849.9			upstream_gene_variant		1	NM_002880.4	P3

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

Gnomad4 AFR exome AF: 0.00168

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.000759

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00178

Gnomad4 NFE exome AF: 0.00516

Gnomad4 OTH exome AF: 0.00208

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

Gnomad4 AFR AF: 0.00112

Gnomad4 AMR AF: 0.00184

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00115

Gnomad4 NFE AF: 0.00537

Gnomad4 OTH AF: 0.000951

Alfa AF: 0.00351 Hom.: 0

Bravo AF: 0.00316

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

Noonan syndrome with multiple lentigines Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Noonan syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 21, 2011

-337_-336delAG in 5'UTR of exon 1 of RAF1: This variant has been identified in o ur laboratory in one individual who is reportedly unaffected with the clinical f eatures of the Noonan spectrum as well as five other probands with Noonan spectr um features who have a pathogenic PTPN11 variant. This variant occurs in the non -coding first exon of the gene. No variants in this region of RAF1 have been sho wn to be pathogenic to date. Therefore, this variant is not expected to have cli nical or pathological significance. -

LEOPARD syndrome 2;C1969057:Noonan syndrome 5;C4014656:Dilated cardiomyopathy 1NN Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 08, 2021

- -

RASopathy Benign:1

Benign, reviewed by expert panel

curation

ClinGen RASopathy Variant Curation Expert Panel

Nov 04, 2019

The c.-339_-338delAG variant in RAF1 is classified as benign because it has been identified in 0.33579% (95% CI of 63/15050) of non-Finnish European alleles in gnomAD (BA1; https://gnomad.broadinstitute.org). This variant is not located within the splice consensus sequence and computational splice site prediction tools do not predict an impact on splicing (BP4, BP7). This variant was identified in 4 individuals with Noonan syndrome who carried additional pathogenic variants in PTPN11 sufficient to explain their clinical presentations (BP5). ACMG/AMP Criteria applied: BA1, BP4, BP5, BP7. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs527774250; hg19: chr3-12705620;