NM_002880.4:c.321-14dupT

Variant names:

• chr3-12609348-T-TA
• rs202103447
• NM_002880.4:c.321-14dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002880.4(RAF1):​c.321-14dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,550,984 control chromosomes in the GnomAD database, including 112 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (96 hom.)
• Consequence: RAF1 NM_002880.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.987
• Publications: 3 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 3-12609348-T-TA is Benign according to our data. Variant chr3-12609348-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0652 is higher than 0.05.

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.321-14dupT		intron	N/A	NP_002871.1
	RAF1	NM_001354689.3		c.321-14dupT		intron	N/A	NP_001341618.1
	RAF1	NM_001354690.3		c.321-14dupT		intron	N/A	NP_001341619.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAF1	ENST00000251849.9	TSL:1 MANE Select	c.321-14_321-13insT		intron	N/A	ENSP00000251849.4
	RAF1	ENST00000442415.7	TSL:5	c.321-14_321-13insT		intron	N/A	ENSP00000401888.2
	RAF1	ENST00000900382.1		c.321-14_321-13insT		intron	N/A	ENSP00000570441.1

Frequencies

GnomAD3 genomes AF: 0.00391 AC: 594 AN: 151892 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00931

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0715

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.000760

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00432

GnomAD2 exomes AF: 0.00939 AC: 2350 AN: 250296 AF XY: 0.00798

Gnomad AFR exome AF: 0.000559

Gnomad AMR exome AF: 0.0266

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0689

Gnomad FIN exome AF: 0.000887

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.00656

GnomAD4 exome AF: 0.00278 AC: 3888 AN: 1398974 Hom.: 96 Cov.: 25 AF XY: 0.00260 AC XY: 1818 AN XY: 699424

African (AFR) AF: 0.000435 AC: 14 AN: 32168

American (AMR) AF: 0.0243 AC: 1085 AN: 44578

Ashkenazi Jewish (ASJ) AF: 0.0000388 AC: 1 AN: 25798

East Asian (EAS) AF: 0.0513 AC: 2020 AN: 39338

South Asian (SAS) AF: 0.00266 AC: 226 AN: 84892

European-Finnish (FIN) AF: 0.00101 AC: 54 AN: 53266

Middle Eastern (MID) AF: 0.000353 AC: 2 AN: 5662

European-Non Finnish (NFE) AF: 0.000180 AC: 190 AN: 1054920

Other (OTH) AF: 0.00507 AC: 296 AN: 58352

GnomAD4 genome AF: 0.00388 AC: 590 AN: 152010 Hom.: 16 Cov.: 32 AF XY: 0.00420 AC XY: 312 AN XY: 74300

African (AFR) AF: 0.000434 AC: 18 AN: 41478

American (AMR) AF: 0.00923 AC: 141 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.0712 AC: 369 AN: 5180

South Asian (SAS) AF: 0.00601 AC: 29 AN: 4822

European-Finnish (FIN) AF: 0.000760 AC: 8 AN: 10530

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 67960

Other (OTH) AF: 0.00428 AC: 9 AN: 2104

Alfa AF: 0.00170 Hom.: 0

Bravo AF: 0.00479

Asia WGS AF: 0.0280 AC: 99 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Noonan syndrome (1)
-	-	1	Noonan syndrome with multiple lentigines (1)
-	-	1	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.99
Mutation Taster		=100/0	polymorphism (auto)

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: rs202103447; hg19: chr3-12650847; COSMIC: COSV52574955; COSMIC: COSV52574955;