chr7-140924774-GGGAGGCGGAGGC-G

Variant names:

• chr7-140924774-GGGAGGCGGAGGC-G
• rs727502907
• NM_001374258.1:c.-83_-72delGCCTCCGCCTCC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001374258.1(BRAF):​c.-83_-72delGCCTCCGCCTCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000985 in 586,848 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_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.

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00047 (1 hom.)
• Consequence: BRAF NM_001374258.1 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P, Genomics England PanelApp
• LEOPARD syndrome 3

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

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00249 (374/150376) while in subpopulation AFR AF = 0.00704 (289/41074). AF 95% confidence interval is 0.00637. There are 0 homozygotes in GnomAd4. There are 180 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 374 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374258.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	NM_001374258.1	MANE Plus Clinical	c.-83_-72delGCCTCCGCCTCC		5_prime_UTR	Exon 1 of 20	NP_001361187.1
	BRAF	NM_004333.6	MANE Select	c.-83_-72delGCCTCCGCCTCC		5_prime_UTR	Exon 1 of 18	NP_004324.2
	BRAF	NM_001374244.1		c.-83_-72delGCCTCCGCCTCC		5_prime_UTR	Exon 1 of 19	NP_001361173.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	ENST00000644969.2	MANE Plus Clinical	c.-83_-72delGCCTCCGCCTCC		5_prime_UTR	Exon 1 of 20	ENSP00000496776.1
	BRAF	ENST00000646891.2	MANE Select	c.-83_-72delGCCTCCGCCTCC		5_prime_UTR	Exon 1 of 18	ENSP00000493543.1
	BRAF	ENST00000496384.7	TSL:5	c.-83_-72delGCCTCCGCCTCC		5_prime_UTR	Exon 1 of 19	ENSP00000419060.2

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 373 AN: 150270 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00706

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00225

Gnomad ASJ AF: 0.00347

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000475

Gnomad OTH AF: 0.00194

GnomAD4 exome AF: 0.000467 AC: 204 AN: 436472 Hom.: 1 AF XY: 0.000442 AC XY: 105 AN XY: 237424

African (AFR) AF: 0.00470 AC: 45 AN: 9578

American (AMR) AF: 0.000715 AC: 12 AN: 16790

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 22 AN: 15198

East Asian (EAS) AF: 0.000127 AC: 3 AN: 23678

South Asian (SAS) AF: 0.000134 AC: 6 AN: 44774

European-Finnish (FIN) AF: 0.000101 AC: 3 AN: 29616

Middle Eastern (MID) AF: 0.00152 AC: 3 AN: 1976

European-Non Finnish (NFE) AF: 0.000310 AC: 84 AN: 270716

Other (OTH) AF: 0.00108 AC: 26 AN: 24146

GnomAD4 genome AF: 0.00249 AC: 374 AN: 150376 Hom.: 0 Cov.: 30 AF XY: 0.00245 AC XY: 180 AN XY: 73504

African (AFR) AF: 0.00704 AC: 289 AN: 41074

American (AMR) AF: 0.00225 AC: 34 AN: 15138

Ashkenazi Jewish (ASJ) AF: 0.00347 AC: 12 AN: 3454

East Asian (EAS) AF: 0.000197 AC: 1 AN: 5070

South Asian (SAS) AF: 0.000418 AC: 2 AN: 4788

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000475 AC: 32 AN: 67390

Other (OTH) AF: 0.00192 AC: 4 AN: 2088

Alfa AF: 0.0000543 Hom.: 0

Bravo AF: 0.00284

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

Other links and lift over

dbSNP: rs727502907; hg19: chr7-140624574;