NM_002880.4:c.*745_*748dupAACA

Variant names:

• chr3-12583765-C-CTGTT
• rs371820097
• NM_002880.4:c.*745_*748dupAACA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_002880.4(RAF1):​c.*745_*748dupAACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 233,452 control chromosomes in the GnomAD database, including 33 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (20 hom., cov: 31)
  • Exomes 𝑓: 0.017 (13 hom.)
• Consequence: RAF1 NM_002880.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.290
• 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]

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0128 (1952/152150) while in subpopulation SAS AF = 0.018 (87/4824). AF 95% confidence interval is 0.0166. There are 20 homozygotes in GnomAd4. There are 976 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 1952 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.*745_*748dupAACA		3_prime_UTR	Exon 17 of 17	NP_002871.1	L7RRS6
	RAF1	NM_001354689.3		c.*745_*748dupAACA		3_prime_UTR	Exon 18 of 18	NP_001341618.1	A0A0S2Z559
	RAF1	NM_001354690.3		c.*745_*748dupAACA		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.*745_*748dupAACA		3_prime_UTR	Exon 17 of 17	ENSP00000251849.4	P04049-1
	RAF1	ENST00000685653.1		c.*745_*748dupAACA		splice_region	Exon 17 of 17	ENSP00000509968.1	P04049-1
	RAF1	ENST00000442415.7	TSL:5	c.*745_*748dupAACA		3_prime_UTR	Exon 18 of 18	ENSP00000401888.2	P04049-2

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1955 AN: 152028 Hom.: 20 Cov.: 31

Gnomad AFR AF: 0.00384

Gnomad AMI AF: 0.0901

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.0490

Gnomad EAS AF: 0.00405

Gnomad SAS AF: 0.0182

Gnomad FIN AF: 0.00321

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0174

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.0174 AC: 1415 AN: 81302 Hom.: 13 Cov.: 0 AF XY: 0.0188 AC XY: 703 AN XY: 37434

African (AFR) AF: 0.00438 AC: 17 AN: 3882

American (AMR) AF: 0.00721 AC: 18 AN: 2498

Ashkenazi Jewish (ASJ) AF: 0.0513 AC: 262 AN: 5110

East Asian (EAS) AF: 0.00493 AC: 56 AN: 11352

South Asian (SAS) AF: 0.0170 AC: 12 AN: 704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 418

Middle Eastern (MID) AF: 0.0224 AC: 11 AN: 492

European-Non Finnish (NFE) AF: 0.0185 AC: 926 AN: 50078

Other (OTH) AF: 0.0167 AC: 113 AN: 6768

GnomAD4 genome AF: 0.0128 AC: 1952 AN: 152150 Hom.: 20 Cov.: 31 AF XY: 0.0131 AC XY: 976 AN XY: 74416

African (AFR) AF: 0.00381 AC: 158 AN: 41478

American (AMR) AF: 0.0118 AC: 180 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0490 AC: 170 AN: 3472

East Asian (EAS) AF: 0.00406 AC: 21 AN: 5178

South Asian (SAS) AF: 0.0180 AC: 87 AN: 4824

European-Finnish (FIN) AF: 0.00321 AC: 34 AN: 10602

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0174 AC: 1186 AN: 67978

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.00418 Hom.: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Noonan syndrome (1)
-	1	-	Noonan syndrome with multiple lentigines (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.29
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs371820097; hg19: chr3-12625264; COSMIC: COSV50104522; COSMIC: COSV50104522;