7-140734590-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP7BP4

This summary comes from the ClinGen Evidence Repository: The c.*7T>C variant in the 3' UTR of BRAF is classified as likely benign because it occurs in a noncoding region, computational splice analyses do not predict an impact on splicing, and Alamut indicates that this nucleotide is not highly conserved (BP4, BP7). It has been identified in 0.0008791% (1/113754) of non-Finnish European chromosomes in gnomAD v2. RASopathy-specific ACMG/AMP Criteria applied (PMID:29493581): BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA175333/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

BRAF
NM_004333.6 3_prime_UTR

Scores

2

Clinical Significance

Likely benign reviewed by expert panel U:3B:2

Conservation

PhyloP100: 0.917
Variant links:
Genes affected
BRAF (HGNC:1097): (B-Raf proto-oncogene, serine/threonine kinase) This gene encodes a protein belonging to the RAF family of serine/threonine protein kinases. This protein plays a role in regulating the MAP kinase/ERK signaling pathway, which affects cell division, differentiation, and secretion. Mutations in this gene, most commonly the V600E mutation, are the most frequently identified cancer-causing mutations in melanoma, and have been identified in various other cancers as well, including non-Hodgkin lymphoma, colorectal cancer, thyroid carcinoma, non-small cell lung carcinoma, hairy cell leukemia and adenocarcinoma of lung. Mutations in this gene are also associated with cardiofaciocutaneous, Noonan, and Costello syndromes, which exhibit overlapping phenotypes. A pseudogene of this gene has been identified on the X chromosome. [provided by RefSeq, Aug 2017]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
BP7

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BRAFNM_004333.6 linkuse as main transcriptc.*7T>C 3_prime_UTR_variant 18/18 ENST00000646891.2
BRAFNM_001374258.1 linkuse as main transcriptc.2401+27T>C intron_variant ENST00000644969.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRAFENST00000646891.2 linkuse as main transcriptc.*7T>C 3_prime_UTR_variant 18/18 NM_004333.6 P4
BRAFENST00000644969.2 linkuse as main transcriptc.2401+27T>C intron_variant NM_001374258.1

Frequencies

GnomAD3 genomes
AF:
0.0000198
AC:
3
AN:
151894
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251476
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135908
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000219
AC:
32
AN:
1461864
Hom.:
0
Cov.:
33
AF XY:
0.0000234
AC XY:
17
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.0000270
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000198
AC:
3
AN:
151894
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74168
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151

ClinVar

Significance: Likely benign
Submissions summary: Uncertain:3Benign:2
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 06, 2010The 2301+7T>C variant in BRAF occurs in the 3' UTR. This variant has not been pr eviously reported in the literature or been identified in our laboratory. This v ariant is not located in a region of high nucleotide conservation; however, this type of variant has not been previously reported as pathogenic in an individual with a Noonan spectrum disorder. The 3'UTR contains regulatory elements essenti al for the regulation and transport of the mRNA transcript, and variants in this region could result in dysregulation or disruption of these functions. While it is likely that this variant is benign, we cannot rule out that it may contribut e to the clinical features observed in this individual. -
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 10, 2023- -
Noonan syndrome 7 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
LEOPARD syndrome 3 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
RASopathy Benign:1
Likely benign, reviewed by expert panelcurationClinGen RASopathy Variant Curation Expert PanelJan 31, 2020The c.*7T>C variant in the 3' UTR of BRAF is classified as likely benign because it occurs in a noncoding region, computational splice analyses do not predict an impact on splicing, and Alamut indicates that this nucleotide is not highly conserved (BP4, BP7). It has been identified in 0.0008791% (1/113754) of non-Finnish European chromosomes in gnomAD v2. RASopathy-specific ACMG/AMP Criteria applied (PMID:29493581): BP4, BP7. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.70
CADD
Benign
10
DANN
Benign
0.85

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.

Other links and lift over

dbSNP: rs727502903; hg19: chr7-140434390; API