7-140924774-GGGAGGC-G

Variant names:

• chr7-140924774-GGGAGGC-G
• rs727502907
• NM_001374258.1:c.-77_-72delGCCTCC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001374258.1(BRAF):​c.-77_-72delGCCTCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000711 in 586,824 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 30)
  • Exomes 𝑓: 0.00051 (0 hom.)
• Consequence: BRAF NM_001374258.1 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00128 (193/150374) while in subpopulation EAS AF = 0.00947 (48/5068). AF 95% confidence interval is 0.00734. There are 1 homozygotes in GnomAd4. There are 98 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 193 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.-77_-72delGCCTCC		5_prime_UTR	Exon 1 of 20	NP_001361187.1
	BRAF	NM_004333.6	MANE Select	c.-77_-72delGCCTCC		5_prime_UTR	Exon 1 of 18	NP_004324.2
	BRAF	NM_001374244.1		c.-77_-72delGCCTCC		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.-77_-72delGCCTCC		5_prime_UTR	Exon 1 of 20	ENSP00000496776.1
	BRAF	ENST00000646891.2	MANE Select	c.-77_-72delGCCTCC		5_prime_UTR	Exon 1 of 18	ENSP00000493543.1
	BRAF	ENST00000496384.7	TSL:5	c.-77_-72delGCCTCC		5_prime_UTR	Exon 1 of 19	ENSP00000419060.2

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 192 AN: 150268 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00126

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00944

Gnomad SAS AF: 0.00250

Gnomad FIN AF: 0.000295

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000727

Gnomad OTH AF: 0.000968

GnomAD4 exome AF: 0.000513 AC: 224 AN: 436450 Hom.: 0 AF XY: 0.000556 AC XY: 132 AN XY: 237406

African (AFR) AF: 0.000626 AC: 6 AN: 9578

American (AMR) AF: 0.000298 AC: 5 AN: 16790

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

East Asian (EAS) AF: 0.00127 AC: 30 AN: 23676

South Asian (SAS) AF: 0.000447 AC: 20 AN: 44774

European-Finnish (FIN) AF: 0.0000675 AC: 2 AN: 29614

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

European-Non Finnish (NFE) AF: 0.000454 AC: 123 AN: 270702

Other (OTH) AF: 0.00145 AC: 35 AN: 24142

GnomAD4 genome AF: 0.00128 AC: 193 AN: 150374 Hom.: 1 Cov.: 30 AF XY: 0.00133 AC XY: 98 AN XY: 73504

African (AFR) AF: 0.00144 AC: 59 AN: 41074

American (AMR) AF: 0.00126 AC: 19 AN: 15138

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

East Asian (EAS) AF: 0.00947 AC: 48 AN: 5068

South Asian (SAS) AF: 0.00272 AC: 13 AN: 4788

European-Finnish (FIN) AF: 0.000295 AC: 3 AN: 10184

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

European-Non Finnish (NFE) AF: 0.000727 AC: 49 AN: 67390

Other (OTH) AF: 0.000958 AC: 2 AN: 2088

Alfa AF: 0.000163 Hom.: 0

Bravo AF: 0.00125

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 26, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. This variant has no t been previously reported in the literature. The BRAF -77_-72del variant repres ents a 6 bp deletion of the final repeat in a repeat sequence upstream of the 5' UTR of BRAF. Our lab has identified this variant in one other individual with No onan spectrum features, and a two repeat deletion in a second individual with No onan spectrum features, out of a total of 756 probands. The other proband with t he single repeat deletion is Black, while the other proband's race is unknown. I n conclusion, the effect, or lack of effect, of this deletion on BRAF promoter a ctivity can not be determined at this time.

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;