Menu
GeneBe

rs727504375

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1PM1PM2PM5PP2PP3_Strong

The NM_001374258.1(BRAF):​c.1569A>T​(p.Lys523Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K523Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

BRAF
NM_001374258.1 missense

Scores

7
5
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.710
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PS1
?
    PS1 - Same amino acid change as a previously established pathogenic variant regardless of nucleotide change
Transcript NM_001374258.1 (BRAF) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 177878
PM1
?
    PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001374258.1
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM5
?
    PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr7-140778061-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
?
    PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, BRAF
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.942

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BRAFNM_001374258.1 linkuse as main transcriptc.1569A>T p.Lys523Asn missense_variant 13/20 ENST00000644969.2
BRAFNM_004333.6 linkuse as main transcriptc.1449A>T p.Lys483Asn missense_variant 12/18 ENST00000646891.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRAFENST00000644969.2 linkuse as main transcriptc.1569A>T p.Lys523Asn missense_variant 13/20 NM_001374258.1
BRAFENST00000646891.2 linkuse as main transcriptc.1449A>T p.Lys483Asn missense_variant 12/18 NM_004333.6 P4
ENST00000700122.1 linkuse as main transcriptn.502+3191T>A intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.29
CADD
Benign
23
DANN
Uncertain
1.0
Eigen
Uncertain
0.50
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.88
D;D;D;D
M_CAP
Pathogenic
0.89
D
MetaRNN
Pathogenic
0.94
D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.91
D
Polyphen
1.0
.;.;D;.
MutPred
0.76
Loss of ubiquitination at K483 (P = 0.0183);.;Loss of ubiquitination at K483 (P = 0.0183);.;
MVP
0.96
MPC
2.3
ClinPred
1.0
D
GERP RS
2.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-140477859; API