chr3-12609348-T-TA

Position:

• chr3-12609348-T-TA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002880.4(RAF1):​c.321-14_321-13insT variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.987

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAF1	NM_002880.4	c.321-14_321-13insT		splice_polypyrimidine_tract_variant, intron_variant		ENST00000251849.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAF1	ENST00000251849.9	c.321-14_321-13insT		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002880.4	P3

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

GnomAD3 exomes AF: 0.00939 AC: 2350 AN: 250296 Hom.: 78 AF XY: 0.00798 AC XY: 1081 AN XY: 135416

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 SAS exome AF: 0.00266

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

Gnomad4 AFR exome AF: 0.000435

Gnomad4 AMR exome AF: 0.0243

Gnomad4 ASJ exome AF: 0.0000388

Gnomad4 EAS exome AF: 0.0513

Gnomad4 SAS exome AF: 0.00266

Gnomad4 FIN exome AF: 0.00101

Gnomad4 NFE exome AF: 0.000180

Gnomad4 OTH exome AF: 0.00507

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

Gnomad4 AFR AF: 0.000434

Gnomad4 AMR AF: 0.00923

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0712

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.000760

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00428

Alfa AF: 0.00170 Hom.: 0

Bravo AF: 0.00479

Asia WGS AF: 0.0280 AC: 99 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2015	c.321-14_321-13insT in intron 3 of RAF1: This variant is not expected to have cl inical significance because it has been identified in 6.7% (573/8544) of East As ian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinst itute.org; dbSNP rs202103447). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2019	Variant summary: RAF1 c.321-14dupT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0088 in 281456 control chromosomes in the gnomAD database, including 81 homozygotes. The observed variant frequency is approximately 350 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAF1 causing Noonan Syndrome and Related Conditions phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.321-14dupT in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2x benign and 1x likely benign). Based on the evidence outlined above, the variant was classified as benign. -

Noonan syndrome with multiple lentigines Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 31, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Noonan syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

RASopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

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: rs202103447; hg19: chr3-12650847;