7-140924774-GGGAGGCGGAGGCGGAGGC-GGGAGGCGGAGGCGGAGGCGGAGGCGGAGGCGGAGGC

Variant names:

• chr7-140924774-G-GGGAGGCGGAGGCGGAGGC
• rs727502907
• NM_001374258.1:c.-89_-72dupGCCTCCGCCTCCGCCTCC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_004333.6(BRAF):​c.-89_-72dupGCCTCCGCCTCCGCCTCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000102 in 586,748 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The gene BRAF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: BRAF NM_004333.6 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• Publications: 0 publications found

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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• LEOPARD syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• Noonan syndrome 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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

ACMG classification

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	NM_001374258.1	MANE Plus Clinical	c.-89_-72dupGCCTCCGCCTCCGCCTCC		5_prime_UTR	Exon 1 of 20	NP_001361187.1	A0A2R8Y8E0
	BRAF	NM_004333.6	MANE Select	c.-89_-72dupGCCTCCGCCTCCGCCTCC		5_prime_UTR	Exon 1 of 18	NP_004324.2
	BRAF	NM_001374244.1		c.-89_-72dupGCCTCCGCCTCCGCCTCC		5_prime_UTR	Exon 1 of 19	NP_001361173.1	A0A2U3TZI2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	ENST00000644969.2	MANE Plus Clinical	c.-89_-72dupGCCTCCGCCTCCGCCTCC		5_prime_UTR	Exon 1 of 20	ENSP00000496776.1	A0A2R8Y8E0
	BRAF	ENST00000646891.2	MANE Select	c.-89_-72dupGCCTCCGCCTCCGCCTCC		5_prime_UTR	Exon 1 of 18	ENSP00000493543.1	P15056
	BRAF	ENST00000912600.1		c.-89_-72dupGCCTCCGCCTCCGCCTCC		5_prime_UTR	Exon 1 of 18	ENSP00000582659.1

Frequencies

GnomAD3 genomes AF: 0.0000200 AC: 3 AN: 150270 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000687 AC: 3 AN: 436478 Hom.: 0 Cov.: 4 AF XY: 0.00000421 AC XY: 1 AN XY: 237428

African (AFR) AF: 0.00 AC: 0 AN: 9578

American (AMR) AF: 0.00 AC: 0 AN: 16792

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15198

East Asian (EAS) AF: 0.00 AC: 0 AN: 23678

South Asian (SAS) AF: 0.00 AC: 0 AN: 44778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1976

European-Non Finnish (NFE) AF: 0.00000739 AC: 2 AN: 270716

Other (OTH) AF: 0.0000414 AC: 1 AN: 24146

GnomAD4 genome AF: 0.0000200 AC: 3 AN: 150270 Hom.: 0 Cov.: 30 AF XY: 0.0000273 AC XY: 2 AN XY: 73390

African (AFR) AF: 0.0000488 AC: 2 AN: 40960

American (AMR) AF: 0.00 AC: 0 AN: 15118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5086

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67400

Other (OTH) AF: 0.00 AC: 0 AN: 2066

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0

Splicing

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.

Other links and lift over

dbSNP: rs727502907;

hg19: chr7-140624574;