rs61730434

Positions:

chr3-12664202-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The variant allele was found at a frequency of 0.00475 in 397,428 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 21 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 3 hom. )

Consequence

intergenic_region

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.93

Variant links:

Genes affected

(HGNC:):

links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 3-12664202-G-C is Benign according to our data. Variant chr3-12664202-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 177923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0103 (1576/152286) while in subpopulation AFR AF= 0.036 (1496/41570). AF 95% confidence interval is 0.0345. There are 21 homozygotes in gnomad4. There are 696 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 21 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
	use as main transcript	n.12664202G>C		intergenic_region

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	Protein	UniProt
RAF1	ENST00000688543.1 linkuse as main transcript	c.-416C>G	upstream_gene_variant		ENSP00000509612.1	A0A0S2Z4L5
RAF1	ENST00000491290.2 linkuse as main transcript	n.-39C>G	upstream_gene_variant	4
RAF1	ENST00000684903.1 linkuse as main transcript	n.-416C>G	upstream_gene_variant		ENSP00000508612.1	A0A8I5KX50

Frequencies

GnomAD3 genomes

AF:

0.0103

AC:

1574

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0360

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00764

GnomAD4 exome

AF:

0.00126

AC:

310

AN:

245142

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

137

AN XY:

124276

show subpopulations

Gnomad4 AFR exome

AF:

0.0337

Gnomad4 AMR exome

AF:

0.00189

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000507

Gnomad4 OTH exome

AF:

0.00288

GnomAD4 genome

AF:

0.0103

AC:

1576

AN:

152286

Hom.:

Cov.:

AF XY:

0.00935

AC XY:

696

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0360

Gnomad4 AMR

AF:

0.00386

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00756

Alfa

AF:

0.00770

Hom.:

Bravo

AF:

0.0119

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Noonan syndrome with multiple lentigines

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 01, 2011

-415-1C>G in the 5'UTR of RAF1: This variant is not expected to have clinical si gnificance because it has been identified in 4.2% of the Yoruba population and i n 1.3% in a mixed population consisting of Caucasian and African American health y females (rs61730434). In addition, it has been identified by our laboratory in four individuals, one of whom also has a pathogenic PTPN11 variant. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 21, 2020

- -

Noonan syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

DANN

Benign

0.83

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over