chr7-140734774-C-A

Variant names:

• chr7-140734774-C-A
• rs956143558
• NM_001374258.1:c.2248-4G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_004333.6(BRAF):​c.2128-4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 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 0.016 (0 hom., cov: 0)
  • Exomes 𝑓: 0.021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BRAF NM_004333.6 splice_region, intron
• Scores: Splicing: ADA: 0.00007941
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.942
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 7-140734774-C-A is Benign according to our data. Variant chr7-140734774-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 377569.

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.2248-4G>T		splice_region intron	N/A	NP_001361187.1	A0A2R8Y8E0
	BRAF	NM_004333.6	MANE Select	c.2128-4G>T		splice_region intron	N/A	NP_004324.2
	BRAF	NM_001374244.1		c.2248-4G>T		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.2248-4G>T		splice_region intron	N/A	ENSP00000496776.1	A0A2R8Y8E0
	BRAF	ENST00000646891.2	MANE Select	c.2128-4G>T		splice_region intron	N/A	ENSP00000493543.1	P15056
	BRAF	ENST00000288602.11	TSL:1	c.2248-4G>T		splice_region intron	N/A	ENSP00000288602.7	A0A2U3TZI2

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 398 AN: 24332 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0303

Gnomad AMI AF: 0.0364

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.00824

Gnomad EAS AF: 0.00764

Gnomad SAS AF: 0.0167

Gnomad FIN AF: 0.00345

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.0238

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0205 AC: 15076 AN: 733840 Hom.: 0 Cov.: 23 AF XY: 0.0191 AC XY: 7061 AN XY: 369880

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

African (AFR) AF: 0.0146 AC: 231 AN: 15850

American (AMR) AF: 0.00374 AC: 57 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00899 AC: 114 AN: 12676

East Asian (EAS) AF: 0.00612 AC: 135 AN: 22058

South Asian (SAS) AF: 0.0113 AC: 406 AN: 35772

European-Finnish (FIN) AF: 0.00547 AC: 129 AN: 23592

Middle Eastern (MID) AF: 0.0136 AC: 36 AN: 2646

European-Non Finnish (NFE) AF: 0.0234 AC: 13470 AN: 575678

Other (OTH) AF: 0.0164 AC: 498 AN: 30322

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0164 AC: 398 AN: 24336 Hom.: 0 Cov.: 0 AF XY: 0.0165 AC XY: 189 AN XY: 11428

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

African (AFR) AF: 0.0303 AC: 161 AN: 5308

American (AMR) AF: 0.0109 AC: 20 AN: 1842

Ashkenazi Jewish (ASJ) AF: 0.00824 AC: 6 AN: 728

East Asian (EAS) AF: 0.00776 AC: 7 AN: 902

South Asian (SAS) AF: 0.0169 AC: 15 AN: 886

European-Finnish (FIN) AF: 0.00345 AC: 4 AN: 1158

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 52

European-Non Finnish (NFE) AF: 0.0133 AC: 174 AN: 13050

Other (OTH) AF: 0.0233 AC: 7 AN: 300

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00978 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	BRAF-related disorder (1)
-	1	-	Intellectual disability (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)
-	-	1	not provided (1)
-	-	1	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.2
DANN	Benign	0.53
PhyloP100		0.94
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000079
dbscSNV1_RF	Benign	0.0060
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: rs956143558; hg19: chr7-140434574;