7-140734774-CAAAAAA-CAAAAAAA

Variant names:

• chr7-140734774-C-CA
• rs373442098
• NM_001374258.1:c.2248-5dupT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_004333.6(BRAF):​c.2128-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 676,340 control chromosomes in the GnomAD database, including 424 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.25 (194 hom., cov: 27)
  • Exomes 𝑓: 0.15 (230 hom.)
• Consequence: BRAF NM_004333.6 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:9 O:1
• Conservation: PhyloP100: 1.19
• Publications: 3 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• LEOPARD syndrome 3

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

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

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 7-140734774-C-CA is Benign according to our data. Variant chr7-140734774-C-CA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44820.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

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.2248-5dupT		splice_region intron	N/A	NP_001361187.1	A0A2R8Y8E0
	BRAF	NM_004333.6	MANE Select	c.2128-5dupT		splice_region intron	N/A	NP_004324.2
	BRAF	NM_001374244.1		c.2248-5dupT		splice_region intron	N/A	NP_001361173.1	A0A2U3TZI2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	ENST00000644969.2	MANE Plus Clinical	c.2248-5_2248-4insT		splice_region intron	N/A	ENSP00000496776.1	A0A2R8Y8E0
	BRAF	ENST00000646891.2	MANE Select	c.2128-5_2128-4insT		splice_region intron	N/A	ENSP00000493543.1	P15056
	BRAF	ENST00000288602.11	TSL:1	c.2248-5_2248-4insT		splice_region intron	N/A	ENSP00000288602.7	A0A2U3TZI2

Frequencies

GnomAD3 genomes AF: 0.246 AC: 5920 AN: 24098 Hom.: 193 Cov.: 27

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.224

GnomAD4 exome AF: 0.146 AC: 95463 AN: 652242 Hom.: 230 Cov.: 28 AF XY: 0.146 AC XY: 47957 AN XY: 328656

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0631 AC: 937 AN: 14852

American (AMR) AF: 0.0962 AC: 1357 AN: 14112

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 1679 AN: 11272

East Asian (EAS) AF: 0.146 AC: 2846 AN: 19492

South Asian (SAS) AF: 0.163 AC: 5238 AN: 32058

European-Finnish (FIN) AF: 0.152 AC: 3269 AN: 21496

Middle Eastern (MID) AF: 0.135 AC: 324 AN: 2394

European-Non Finnish (NFE) AF: 0.149 AC: 75702 AN: 509494

Other (OTH) AF: 0.152 AC: 4111 AN: 27072

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.245 AC: 5915 AN: 24098 Hom.: 194 Cov.: 27 AF XY: 0.238 AC XY: 2684 AN XY: 11266

African (AFR) AF: 0.117 AC: 629 AN: 5360

American (AMR) AF: 0.214 AC: 393 AN: 1834

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 215 AN: 714

East Asian (EAS) AF: 0.253 AC: 225 AN: 890

South Asian (SAS) AF: 0.265 AC: 234 AN: 882

European-Finnish (FIN) AF: 0.198 AC: 227 AN: 1146

Middle Eastern (MID) AF: 0.385 AC: 20 AN: 52

European-Non Finnish (NFE) AF: 0.303 AC: 3887 AN: 12818

Other (OTH) AF: 0.216 AC: 64 AN: 296

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (6)
-	-	2	not provided (2)
-	1	-	Cardio-facio-cutaneous syndrome (1)
-	1	-	Congenital long QT syndrome (1)
-	1	-	Noonan syndrome (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)
-	1	-	Noonan syndrome with multiple lentigines (1)
-	-	1	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism

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: rs373442098; hg19: chr7-140434574; COSMIC: COSV56184569;