7-140924774-GGGAGGCGGAGGCGGAGGC-GGGAGGCGGAGGC

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_004333.6(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_004333.6 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00

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]

ACMG classification

Verdict is Likely_benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 193 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.-77_-72delGCCTCC		5_prime_UTR_variant	Exon 1 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.-77_-72delGCCTCC		5_prime_UTR_variant	Exon 1 of 18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.-77_-72delGCCTCC		5_prime_UTR_variant	Exon 1 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.-77_-72delGCCTCC		5_prime_UTR_variant	Exon 1 of 18		NM_004333.6	ENSP00000493543.1

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

Gnomad4 AFR exome AF: 0.000626

Gnomad4 AMR exome AF: 0.000298

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00127

Gnomad4 SAS exome AF: 0.000447

Gnomad4 FIN exome AF: 0.0000675

Gnomad4 NFE exome AF: 0.000454

Gnomad4 OTH exome AF: 0.00145

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

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.00126

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00947

Gnomad4 SAS AF: 0.00272

Gnomad4 FIN AF: 0.000295

Gnomad4 NFE AF: 0.000727

Gnomad4 OTH AF: 0.000958

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 v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs727502907; hg19: chr7-140624574;