7-140808351-CAAAAAAAAAAAAAAAA-CAAAAAAAAAAAAA

Variant names:

Variant summary

Our verdict is . The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_004333.6(BRAF):c.609-292_609-290delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0645 in 190,242 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★). The gene BRAF is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 21)

Exomes 𝑓: 0.083 ( 0 hom. )

Consequence

BRAF
NM_004333.6 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.450

Publications

1 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Ambry Genetics, PanelApp Australia
LEOPARD syndrome 3
Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
Noonan syndrome 7
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Ambry Genetics, PanelApp Australia
large congenital melanocytic nevus
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
Noonan syndrome
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
Noonan syndrome with multiple lentigines
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen
anaplastic astrocytoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
Costello syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

BRAF links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_004333.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Specifications for BRAF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant 7-140808351-CAAA-C is Benign according to our data. Variant chr7-140808351-CAAA-C is described in ClinVar as Benign. ClinVar VariationId is 1237833.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000997 (42/42110) while in subpopulation AFR AF = 0.00253 (35/13848). AF 95% confidence interval is 0.00187. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

BS2

High AC in GnomAd4 at 42 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	Effect	Exon Rank	Protein	UniProt
BRAF	NM_001374258.1	MANE Plus Clinical	c.609-292_609-290delTTT	intron	N/A	NP_001361187.1	A0A2R8Y8E0
BRAF	NM_004333.6	MANE Select	c.609-292_609-290delTTT	intron	N/A	NP_004324.2
BRAF	NM_001374244.1		c.609-292_609-290delTTT	intron	N/A	NP_001361173.1	A0A2U3TZI2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
BRAF	ENST00000644969.2	MANE Plus Clinical	c.609-292_609-290delTTT	intron	N/A	ENSP00000496776.1	A0A2R8Y8E0
BRAF	ENST00000646891.2	MANE Select	c.609-292_609-290delTTT	intron	N/A	ENSP00000493543.1	P15056
BRAF	ENST00000288602.11	TSL:1	c.609-292_609-290delTTT	intron	N/A	ENSP00000288602.7	A0A2U3TZI2

Frequencies

GnomAD3 genomes

AF:

0.000997

AC:

AN:

42124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00253

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00400

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000787

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000527

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0793

AC:

1821

AN:

22952

AF XY:

0.0727

show subpopulations

Gnomad AFR exome

AF:

0.139

Gnomad AMR exome

AF:

0.109

Gnomad ASJ exome

AF:

0.0476

Gnomad EAS exome

AF:

0.113

Gnomad FIN exome

AF:

0.0518

Gnomad NFE exome

AF:

0.0640

Gnomad OTH exome

AF:

0.0822

GnomAD4 exome

AF:

0.0825

AC:

12222

AN:

148132

Hom.:

AF XY:

0.0807

AC XY:

7019

AN XY:

86996

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.107

AC:

305

AN:

2846

American (AMR)

AF:

0.0877

AC:

630

AN:

7184

Ashkenazi Jewish (ASJ)

AF:

0.0605

AC:

251

AN:

4148

East Asian (EAS)

AF:

0.0863

AC:

411

AN:

4762

South Asian (SAS)

AF:

0.0816

AC:

2302

AN:

28210

European-Finnish (FIN)

AF:

0.0786

AC:

500

AN:

6362

Middle Eastern (MID)

AF:

0.0833

AC:

AN:

600

European-Non Finnish (NFE)

AF:

0.0825

AC:

7194

AN:

87202

Other (OTH)

AF:

0.0849

AC:

579

AN:

6818

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.312

Heterozygous variant carriers

838

1676

2515

3353

4191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

112

168

224

280

<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:

0.000997

AC:

AN:

42110

Hom.:

Cov.:

AF XY:

0.00122

AC XY:

AN XY:

19720

show subpopulations

African (AFR)

AF:

0.00253

AC:

AN:

13848

American (AMR)

AF:

0.00

AC:

AN:

3258

Ashkenazi Jewish (ASJ)

AF:

0.00400

AC:

AN:

1250

East Asian (EAS)

AF:

0.00

AC:

AN:

1268

South Asian (SAS)

AF:

0.00

AC:

AN:

1356

European-Finnish (FIN)

AF:

0.000787

AC:

AN:

1270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0000527

AC:

AN:

18958

Other (OTH)

AF:

0.00

AC:

AN:

546

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.45

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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