NM_002880.4:c.*628G>A

Variant names:

• chr3-12583886-C-T
• rs374944110
• NM_002880.4:c.*628G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002880.4(RAF1):​c.*628G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000851 in 234,944 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. The gene RAF1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: RAF1 NM_002880.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0840
• Publications: 1 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]

MKRN2 (HGNC:7113): (makorin ring finger protein 2) This gene encodes a probable E3 ubiquitin ligase containing several zinc finger domains, that is a member of the makorin RING zinc-finger protein family. This gene overlaps the v-raf-1 murine leukemia viral oncogene homolog 1 (RAF1) gene in an antisense orientation and may have a co-regulatory function with RAF1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

ACMG classification

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS2: High AC in GnomAd4 at 10 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAF1	NM_002880.4	MANE Select	c.*628G>A		3_prime_UTR	Exon 17 of 17	NP_002871.1	L7RRS6
	RAF1	NM_001354689.3		c.*628G>A		3_prime_UTR	Exon 18 of 18	NP_001341618.1	A0A0S2Z559
	RAF1	NM_001354690.3		c.*628G>A		3_prime_UTR	Exon 17 of 17	NP_001341619.1	P04049-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAF1	ENST00000251849.9	TSL:1 MANE Select	c.*628G>A		3_prime_UTR	Exon 17 of 17	ENSP00000251849.4	P04049-1
	RAF1	ENST00000442415.7	TSL:5	c.*628G>A		3_prime_UTR	Exon 18 of 18	ENSP00000401888.2	P04049-2
	RAF1	ENST00000900382.1		c.*628G>A		3_prime_UTR	Exon 18 of 18	ENSP00000570441.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000121 AC: 10 AN: 82626 Hom.: 0 Cov.: 0 AF XY: 0.000105 AC XY: 4 AN XY: 38118

African (AFR) AF: 0.00 AC: 0 AN: 3900

American (AMR) AF: 0.00 AC: 0 AN: 2758

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5124

East Asian (EAS) AF: 0.000789 AC: 9 AN: 11414

South Asian (SAS) AF: 0.00 AC: 0 AN: 772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 488

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 492

European-Non Finnish (NFE) AF: 0.0000197 AC: 1 AN: 50864

Other (OTH) AF: 0.00 AC: 0 AN: 6814

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74482

African (AFR) AF: 0.0000722 AC: 3 AN: 41578

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.2
DANN	Benign	0.49
PhyloP100		0.084
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs374944110; hg19: chr3-12625385;