rs10487888

Variant names:

• chr7-140799307-C-T
• rs10487888
• NM_001374258.1:c.980+1055G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001374258.1(BRAF):​c.980+1055G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 232,174 control chromosomes in the GnomAD database, including 21,838 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.37 (13201 hom., cov: 32)
  • Exomes 𝑓: 0.43 (8637 hom.)
• Consequence: BRAF NM_001374258.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.129
• Publications: 22 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.980+1055G>A		intron_variant	Intron 7 of 19	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.980+1055G>A		intron_variant	Intron 7 of 17	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.980+1055G>A		intron_variant	Intron 7 of 19		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.980+1055G>A		intron_variant	Intron 7 of 17		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55680 AN: 151888 Hom.: 13204 Cov.: 32

Gnomad AFR AF: 0.0988

Gnomad AMI AF: 0.408

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.403

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.502

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.541

Gnomad OTH AF: 0.395

GnomAD4 exome AF: 0.429 AC: 34386 AN: 80168 Hom.: 8637 Cov.: 0 AF XY: 0.435 AC XY: 16036 AN XY: 36864

African (AFR) AF: 0.0933 AC: 361 AN: 3868

American (AMR) AF: 0.294 AC: 730 AN: 2480

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 2072 AN: 5100

East Asian (EAS) AF: 0.112 AC: 1264 AN: 11270

South Asian (SAS) AF: 0.201 AC: 139 AN: 692

European-Finnish (FIN) AF: 0.452 AC: 28 AN: 62

Middle Eastern (MID) AF: 0.408 AC: 200 AN: 490

European-Non Finnish (NFE) AF: 0.539 AC: 26680 AN: 49506

Other (OTH) AF: 0.435 AC: 2912 AN: 6700

GnomAD4 genome AF: 0.366 AC: 55667 AN: 152006 Hom.: 13201 Cov.: 32 AF XY: 0.360 AC XY: 26717 AN XY: 74274

African (AFR) AF: 0.0985 AC: 4087 AN: 41494

American (AMR) AF: 0.333 AC: 5087 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 1396 AN: 3466

East Asian (EAS) AF: 0.156 AC: 810 AN: 5180

South Asian (SAS) AF: 0.199 AC: 959 AN: 4822

European-Finnish (FIN) AF: 0.502 AC: 5286 AN: 10520

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.541 AC: 36738 AN: 67946

Other (OTH) AF: 0.392 AC: 827 AN: 2110

Alfa AF: 0.492 Hom.: 49322

Bravo AF: 0.344

Asia WGS AF: 0.171 AC: 595 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.1
DANN	Benign	0.71
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs10487888; hg19: chr7-140499107;