7-140734774-CAAAAAA-CAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_004333.6(BRAF):​c.2128-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0345 in 713,756 control chromosomes in the GnomAD database, including 16 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (3 hom., cov: 27)
  • Exomes 𝑓: 0.035 (13 hom.)
• Consequence: BRAF NM_004333.6 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• 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 -16 ACMG points.

• BP6: Variant 7-140734774-CA-C is Benign according to our data. Variant chr7-140734774-CA-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0118 (290/24564) while in subpopulation NFE AF = 0.0164 (215/13132). AF 95% confidence interval is 0.0146. There are 3 homozygotes in GnomAd4. There are 131 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High AC in GnomAd4 at 290 AD gene.

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.2248-5delT		splice_region intron	N/A	NP_001361187.1	A0A2R8Y8E0
	BRAF	NM_004333.6	MANE Select	c.2128-5delT		splice_region intron	N/A	NP_004324.2
	BRAF	NM_001374244.1		c.2248-5delT		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.2248-5delT		splice_region intron	N/A	ENSP00000496776.1	A0A2R8Y8E0
	BRAF	ENST00000646891.2	MANE Select	c.2128-5delT		splice_region intron	N/A	ENSP00000493543.1	P15056
	BRAF	ENST00000288602.11	TSL:1	c.2248-5delT		splice_region intron	N/A	ENSP00000288602.7	A0A2U3TZI2

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 291 AN: 24562 Hom.: 3 Cov.: 27

Gnomad AFR AF: 0.00741

Gnomad AMI AF: 0.0179

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.00137

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000862

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0165

Gnomad OTH AF: 0.0236

GnomAD4 exome AF: 0.0353 AC: 24361 AN: 689192 Hom.: 13 Cov.: 28 AF XY: 0.0349 AC XY: 12125 AN XY: 347002

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

African (AFR) AF: 0.0376 AC: 542 AN: 14416

American (AMR) AF: 0.0358 AC: 506 AN: 14124

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 406 AN: 11838

East Asian (EAS) AF: 0.0455 AC: 912 AN: 20036

South Asian (SAS) AF: 0.0314 AC: 1049 AN: 33388

European-Finnish (FIN) AF: 0.0398 AC: 875 AN: 21984

Middle Eastern (MID) AF: 0.0308 AC: 77 AN: 2500

European-Non Finnish (NFE) AF: 0.0348 AC: 18885 AN: 542644

Other (OTH) AF: 0.0392 AC: 1109 AN: 28262

⚠️ 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: 0.0118 AC: 290 AN: 24564 Hom.: 3 Cov.: 27 AF XY: 0.0114 AC XY: 131 AN XY: 11516

African (AFR) AF: 0.00738 AC: 40 AN: 5418

American (AMR) AF: 0.0129 AC: 24 AN: 1854

Ashkenazi Jewish (ASJ) AF: 0.00137 AC: 1 AN: 732

East Asian (EAS) AF: 0.00 AC: 0 AN: 908

South Asian (SAS) AF: 0.00 AC: 0 AN: 894

European-Finnish (FIN) AF: 0.000862 AC: 1 AN: 1160

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

European-Non Finnish (NFE) AF: 0.0164 AC: 215 AN: 13132

Other (OTH) AF: 0.0232 AC: 7 AN: 302

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	1	Cardio-facio-cutaneous 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		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: COSV56304400;