Genetic Variant BRAF:p.Asp22Asn (chr7-140924640-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_004333.6(BRAF):c.64G>A(p.Asp22Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 1,482,198 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D22V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00024 ( 3 hom. )

Consequence

BRAF
NM_004333.6 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:11O:1

Conservation

PhyloP100: 2.38

Publications

39 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 -19 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 cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, Noonan syndrome, cardiofaciocutaneous syndrome 1, Noonan syndrome 7, LEOPARD syndrome 3, anaplastic astrocytoma, Costello syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.007866472).

BP6

Variant 7-140924640-C-T is Benign according to our data. Variant chr7-140924640-C-T is described in ClinVar as Benign. ClinVar VariationId is 40335.Status of the report is reviewed_by_expert_panel, 3 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000298 (45/151046) while in subpopulation EAS AF = 0.00878 (44/5014). AF 95% confidence interval is 0.00672. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 45 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.64G>A	p.Asp22Asn	missense	Exon 1 of 20	NP_001361187.1	A0A2R8Y8E0
BRAF	NM_004333.6	MANE Select	c.64G>A	p.Asp22Asn	missense	Exon 1 of 18	NP_004324.2
BRAF	NM_001374244.1		c.64G>A	p.Asp22Asn	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.64G>A	p.Asp22Asn	missense	Exon 1 of 20	ENSP00000496776.1	A0A2R8Y8E0
BRAF	ENST00000646891.2	MANE Select	c.64G>A	p.Asp22Asn	missense	Exon 1 of 18	ENSP00000493543.1	P15056
BRAF	ENST00000288602.11	TSL:1	c.64G>A	p.Asp22Asn	missense	Exon 1 of 19	ENSP00000288602.7	A0A2U3TZI2

Frequencies

GnomAD3 genomes

AF:

0.000305

AC:

AN:

150932

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:

0.00895

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000729

AC:

AN:

124868

AF XY:

0.000714

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00881

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000257

GnomAD4 exome

AF:

0.000245

AC:

326

AN:

1331152

Hom.:

Cov.:

AF XY:

0.000253

AC XY:

167

AN XY:

659446

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29970

American (AMR)

AF:

0.00

AC:

AN:

35138

Ashkenazi Jewish (ASJ)

AF:

0.0000812

AC:

AN:

24644

East Asian (EAS)

AF:

0.00779

AC:

274

AN:

35180

South Asian (SAS)

AF:

0.000154

AC:

AN:

77996

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33132

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4008

European-Non Finnish (NFE)

AF:

0.00000869

AC:

AN:

1035180

Other (OTH)

AF:

0.000519

AC:

AN:

55904

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000298

AC:

AN:

151046

Hom.:

Cov.:

AF XY:

0.000379

AC XY:

AN XY:

73822

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41258

American (AMR)

AF:

0.00

AC:

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00878

AC:

AN:

5014

South Asian (SAS)

AF:

0.000209

AC:

AN:

4788

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10464

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67536

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.000285

Hom.:

Bravo

AF:

0.000491

ExAC

AF:

0.0000322

AC:

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

RASopathy (2)

BRAF-related disorder (1)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Noonan syndrome and Noonan-related syndrome (1)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

Eigen

Benign

0.033

Eigen_PC

Benign

0.083

FATHMM_MKL

Benign

0.47

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.0079

MetaSVM

Benign

-0.70

MutationAssessor

Benign

0.69

PhyloP100

2.4

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

-0.49

REVEL

Benign

0.25

Sift

Benign

0.20

Sift4G

Benign

0.21

Polyphen

0.81

Vest4

0.38

MVP

0.67

MPC

0.92

ClinPred

0.13

GERP RS

3.2

PromoterAI

0.17

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.41

Mutation Taster

=91/9

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