chr7-140808351-C-CA

Variant names:

Variant summary

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

The NM_004333.6(BRAF):c.609-290dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0332 in 198,282 control chromosomes in the GnomAD database, including 40 homozygotes. Variant has been reported in ClinVar as Likely benign (★). The gene BRAF is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.028 ( 38 hom., cov: 21)

Exomes 𝑓: 0.034 ( 2 hom. )

Consequence

BRAF
NM_004333.6 intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.618

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-C-CA is Benign according to our data. Variant chr7-140808351-C-CA is described in ClinVar as Likely_benign. ClinVar VariationId is 1202093.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0285 (1196/42012) while in subpopulation EAS AF = 0.0452 (57/1262). AF 95% confidence interval is 0.0375. There are 38 homozygotes in GnomAd4. There are 524 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

BS2

High AC in GnomAd4 at 1196 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.609-290dupT	intron	N/A	NP_001361187.1	A0A2R8Y8E0
BRAF	NM_004333.6	MANE Select	c.609-290dupT	intron	N/A	NP_004324.2
BRAF	NM_001374244.1		c.609-290dupT	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.609-290_609-289insT	intron	N/A	ENSP00000496776.1	A0A2R8Y8E0
BRAF	ENST00000646891.2	MANE Select	c.609-290_609-289insT	intron	N/A	ENSP00000493543.1	P15056
BRAF	ENST00000288602.11	TSL:1	c.609-290_609-289insT	intron	N/A	ENSP00000288602.7	A0A2U3TZI2

Frequencies

GnomAD3 genomes

AF:

0.0284

AC:

1193

AN:

42026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0127

Gnomad AMI

AF:

0.00775

Gnomad AMR

AF:

0.0188

Gnomad ASJ

AF:

0.0362

Gnomad EAS

AF:

0.0442

Gnomad SAS

AF:

0.0344

Gnomad FIN

AF:

0.0205

Gnomad MID

AF:

0.0204

Gnomad NFE

AF:

0.0399

Gnomad OTH

AF:

0.0444

GnomAD2 exomes

AF:

0.0193

AC:

444

AN:

22952

AF XY:

0.0178

show subpopulations

Gnomad AFR exome

AF:

0.0178

Gnomad AMR exome

AF:

0.0281

Gnomad ASJ exome

AF:

0.0134

Gnomad EAS exome

AF:

0.0305

Gnomad FIN exome

AF:

0.0113

Gnomad NFE exome

AF:

0.0142

Gnomad OTH exome

AF:

0.0237

GnomAD4 exome

AF:

0.0345

AC:

5385

AN:

156270

Hom.:

Cov.:

AF XY:

0.0346

AC XY:

3177

AN XY:

91854

show subpopulations

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

African (AFR)

AF:

0.0184

AC:

AN:

2996

American (AMR)

AF:

0.0329

AC:

249

AN:

7560

Ashkenazi Jewish (ASJ)

AF:

0.0251

AC:

107

AN:

4270

East Asian (EAS)

AF:

0.0328

AC:

167

AN:

5092

South Asian (SAS)

AF:

0.0324

AC:

956

AN:

29498

European-Finnish (FIN)

AF:

0.0387

AC:

259

AN:

6700

Middle Eastern (MID)

AF:

0.0244

AC:

AN:

614

European-Non Finnish (NFE)

AF:

0.0362

AC:

3341

AN:

92368

Other (OTH)

AF:

0.0329

AC:

236

AN:

7172

⚠️ 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: 0.371

Heterozygous variant carriers

254

507

761

1014

1268

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<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:

0.0285

AC:

1196

AN:

42012

Hom.:

Cov.:

AF XY:

0.0266

AC XY:

524

AN XY:

19680

show subpopulations

African (AFR)

AF:

0.0128

AC:

177

AN:

13842

American (AMR)

AF:

0.0188

AC:

AN:

3250

Ashkenazi Jewish (ASJ)

AF:

0.0362

AC:

AN:

1244

East Asian (EAS)

AF:

0.0452

AC:

AN:

1262

South Asian (SAS)

AF:

0.0348

AC:

AN:

1352

European-Finnish (FIN)

AF:

0.0205

AC:

AN:

1270

Middle Eastern (MID)

AF:

0.0213

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0399

AC:

754

AN:

18896

Other (OTH)

AF:

0.0460

AC:

AN:

544

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

131

175

219

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:Likely 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

-0.62

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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