rs727504398

Variant names:

• chr3-12663955-C-A
• rs727504398
• NM_002880.4:c.-169G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-12663955-C-A
• chr3-12663955-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002880.4(RAF1):​c.-169G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000122 in 246,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: RAF1 NM_002880.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.41
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).

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.-169G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	NP_002871.1
	RAF1	NM_002880.4	MANE Select	c.-169G>T		5_prime_UTR	Exon 1 of 17	NP_002871.1
	RAF1	NM_001354689.3		c.-169G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 18	NP_001341618.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAF1	ENST00000251849.9	TSL:1 MANE Select	c.-169G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	ENSP00000251849.4
	RAF1	ENST00000251849.9	TSL:1 MANE Select	c.-169G>T		5_prime_UTR	Exon 1 of 17	ENSP00000251849.4
	RAF1	ENST00000442415.7	TSL:5	c.-169G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 18	ENSP00000401888.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000122 AC: 3 AN: 246130 Hom.: 0 Cov.: 0 AF XY: 0.0000160 AC XY: 2 AN XY: 124754

African (AFR) AF: 0.00 AC: 0 AN: 7166

American (AMR) AF: 0.00 AC: 0 AN: 7432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9228

East Asian (EAS) AF: 0.00 AC: 0 AN: 22886

South Asian (SAS) AF: 0.00 AC: 0 AN: 3030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1294

European-Non Finnish (NFE) AF: 0.0000127 AC: 2 AN: 157908

Other (OTH) AF: 0.0000611 AC: 1 AN: 16362

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	17
DANN	Benign	0.80
PhyloP100		1.4
PromoterAI		-0.052	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

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

Other links and lift over

dbSNP: rs727504398; hg19: chr3-12705454;