Genetic Variant BRAF:p.Met23Lys (chr7-140924636-A-T) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 1P and 18B. PP2BP4_ModerateBP6_Very_StrongBS1BS2

The NM_004333.6(BRAF):c.68T>A(p.Met23Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,490,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M23V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

BRAF
NM_004333.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:2

Conservation

PhyloP100: 1.75

Publications

3 publications found

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]

BRAF Gene-Disease associations (from GenCC):

cardiofaciocutaneous syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
cardiofaciocutaneous syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
LEOPARD syndrome 3
Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
Noonan syndrome 7
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
Noonan syndrome
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
Noonan syndrome with multiple lentigines
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet
anaplastic astrocytoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
Costello syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Noonan syndrome-like disorder with loose anagen hair
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

BRAF links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PP2

Missense variant in the BRAF gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 139 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. Gene score misZ: 3.7208 (above the threshold of 3.09). Trascript score misZ: 4.9447 (above the threshold of 3.09). GenCC associations: The gene is linked to LEOPARD syndrome 3, Costello syndrome, Noonan syndrome 7, Noonan syndrome-like disorder with loose anagen hair, cardiofaciocutaneous syndrome 1, cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, Noonan syndrome, anaplastic astrocytoma.

BP4

Computational evidence support a benign effect (MetaRNN=0.19695663).

BP6

Variant 7-140924636-A-T is Benign according to our data. Variant chr7-140924636-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 579533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000246 (33/1340936) while in subpopulation SAS AF = 0.000421 (33/78352). AF 95% confidence interval is 0.000308. There are 0 homozygotes in GnomAdExome4. There are 29 alleles in the male GnomAdExome4 subpopulation. Median coverage is 26. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 33 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004333.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BRAF	NM_001374258.1	MANE Plus Clinical	c.68T>A	p.Met23Lys	missense	Exon 1 of 20	NP_001361187.1	A0A2R8Y8E0
BRAF	NM_004333.6	MANE Select	c.68T>A	p.Met23Lys	missense	Exon 1 of 18	NP_004324.2
BRAF	NM_001374244.1		c.68T>A	p.Met23Lys	missense	Exon 1 of 19	NP_001361173.1	A0A2U3TZI2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BRAF	ENST00000644969.2	MANE Plus Clinical	c.68T>A	p.Met23Lys	missense	Exon 1 of 20	ENSP00000496776.1	A0A2R8Y8E0
BRAF	ENST00000646891.2	MANE Select	c.68T>A	p.Met23Lys	missense	Exon 1 of 18	ENSP00000493543.1	P15056
BRAF	ENST00000288602.11	TSL:1	c.68T>A	p.Met23Lys	missense	Exon 1 of 19	ENSP00000288602.7	A0A2U3TZI2

Frequencies

GnomAD3 genomes

AF:

0.00000668

AC:

AN:

149594

Hom.:

Cov.:

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:

0.000217

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000795

AC:

AN:

125838

AF XY:

0.000116

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1340936

Hom.:

Cov.:

AF XY:

0.0000437

AC XY:

AN XY:

663662

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30188

American (AMR)

AF:

0.00

AC:

AN:

35030

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24488

East Asian (EAS)

AF:

0.00

AC:

AN:

34852

South Asian (SAS)

AF:

0.000421

AC:

AN:

78352

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32114

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4004

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1046058

Other (OTH)

AF:

0.00

AC:

AN:

55850

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000134

AC:

AN:

149708

Hom.:

Cov.:

AF XY:

0.0000273

AC XY:

AN XY:

73162

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40922

American (AMR)

AF:

0.00

AC:

AN:

15120

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

4840

South Asian (SAS)

AF:

0.000434

AC:

AN:

4612

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10236

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67226

Other (OTH)

AF:

0.00

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000918

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3470

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

BRAF-related disorder (1)

not specified (1)

RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.33

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.72

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.0

PhyloP100

1.7

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

-0.61

REVEL

Uncertain

0.42

Sift

Uncertain

0.023

Sift4G

Benign

0.070

Polyphen

0.018

Vest4

0.80

MutPred

0.28

Gain of ubiquitination at M23 (P = 0.0016)

MVP

0.99

MPC

1.4

ClinPred

0.16

GERP RS

3.2

PromoterAI

0.011

Neutral

(source)

Varity_R

0.81

gMVP

0.70

Mutation Taster

=71/29

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over