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). The gene BRAF is included in the ClinGen Criteria Specification Registry.

• 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

Specifications for BRAF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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;