chr3-12664053-C-T

Position:

• chr3-12664053-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4 BA1 BP7 BP5

This summary comes from the ClinGen Evidence Repository: The c.-267G>A variant was identified in the RAF1 gene. The filtering allele frequency for the c.-267G>A is 6.32% for African chromosomes in gnomAD (68/8706 with 95% CI) (https://gnomad.broadinstitute.org/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). The variant has also been identified in a patient with an alternate molecular basis for disease (BP5; Laboratory for Molecular Medicine internal data). In summary, the c.-267G>A variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BA1, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA181005/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: RAF1 NM_002880.4 5_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: 0.505

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAF1	NM_002880.4	c.-267G>A		5_prime_UTR_variant	1/17	ENST00000251849.9	NP_002871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAF1	ENST00000251849.9	c.-267G>A		5_prime_UTR_variant	1/17	1	NM_002880.4	ENSP00000251849.4

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 304 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00685

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.000357 AC: 88 AN: 246212 Hom.: 0 Cov.: 0 AF XY: 0.000345 AC XY: 43 AN XY: 124792

Gnomad4 AFR exome AF: 0.00655

Gnomad4 AMR exome AF: 0.000404

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000133

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.00200 AC: 305 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.00200 AC XY: 149 AN XY: 74474

Gnomad4 AFR AF: 0.00686

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00189

Bravo AF: 0.00214

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 17, 2011

This variant is located in the 5'UTR and variants in regulatory regions could ha ve an effect on transcriptional or translational efficiency. However, variants o f this type have not been reported in Noonan spectrum disorders to date. In addi tion, this variant has now been identified in 2/58 (3.4%) Black probands tested by our laboratory, including one proband with a pathogenic PTPN11 variant. This variant may be common in the Black population and therefore unlikely to be patho genic. -

LEOPARD syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

RASopathy Benign:1

Benign, reviewed by expert panel

curation

ClinGen RASopathy Variant Curation Expert Panel

Jul 25, 2019

The c.-267G>A variant was identified in the RAF1 gene. The filtering allele frequency for the c.-267G>A is 6.32% for African chromosomes in gnomAD (68/8706 with 95% CI) (https://gnomad.broadinstitute.org/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). The variant has also been identified in a patient with an alternate molecular basis for disease (BP5; Laboratory for Molecular Medicine internal data). In summary, the c.-267G>A variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BA1, BP5. -

Noonan syndrome 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.6
DANN	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs116247741; hg19: chr3-12705552;