NM_001374258.1:c.980+27G>A

Variant names:

• chr7-140800335-C-T
• rs41282721
• NM_001374258.1:c.980+27G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001374258.1(BRAF):​c.980+27G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0704 in 1,613,628 control chromosomes in the GnomAD database, including 4,526 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (291 hom., cov: 32)
  • Exomes 𝑓: 0.072 (4235 hom.)
• Consequence: BRAF NM_001374258.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0360
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-140800335-C-T is Benign according to our data. Variant chr7-140800335-C-T is described in ClinVar as Benign. ClinVar VariationId is 40354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374258.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	NM_001374258.1	MANE Plus Clinical	c.980+27G>A		intron	N/A	NP_001361187.1
	BRAF	NM_004333.6	MANE Select	c.980+27G>A		intron	N/A	NP_004324.2
	BRAF	NM_001374244.1		c.980+27G>A		intron	N/A	NP_001361173.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	ENST00000644969.2	MANE Plus Clinical	c.980+27G>A		intron	N/A	ENSP00000496776.1
	BRAF	ENST00000646891.2	MANE Select	c.980+27G>A		intron	N/A	ENSP00000493543.1
	BRAF	ENST00000288602.11	TSL:1	c.980+27G>A		intron	N/A	ENSP00000288602.7

Frequencies

GnomAD3 genomes AF: 0.0565 AC: 8589 AN: 152080 Hom.: 290 Cov.: 32

Gnomad AFR AF: 0.0219

Gnomad AMI AF: 0.0374

Gnomad AMR AF: 0.0531

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.0837

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.0587

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0693

Gnomad OTH AF: 0.0608

GnomAD2 exomes AF: 0.0700 AC: 17587 AN: 251312 AF XY: 0.0760

Gnomad AFR exome AF: 0.0194

Gnomad AMR exome AF: 0.0317

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.0948

Gnomad FIN exome AF: 0.0622

Gnomad NFE exome AF: 0.0717

Gnomad OTH exome AF: 0.0708

GnomAD4 exome AF: 0.0719 AC: 105025 AN: 1461430 Hom.: 4235 Cov.: 31 AF XY: 0.0741 AC XY: 53900 AN XY: 727040

African (AFR) AF: 0.0180 AC: 601 AN: 33466

American (AMR) AF: 0.0352 AC: 1576 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 2800 AN: 26128

East Asian (EAS) AF: 0.0834 AC: 3309 AN: 39692

South Asian (SAS) AF: 0.113 AC: 9763 AN: 86230

European-Finnish (FIN) AF: 0.0591 AC: 3154 AN: 53376

Middle Eastern (MID) AF: 0.123 AC: 704 AN: 5702

European-Non Finnish (NFE) AF: 0.0708 AC: 78669 AN: 1111762

Other (OTH) AF: 0.0737 AC: 4449 AN: 60364

GnomAD4 genome AF: 0.0564 AC: 8588 AN: 152198 Hom.: 291 Cov.: 32 AF XY: 0.0572 AC XY: 4253 AN XY: 74410

African (AFR) AF: 0.0219 AC: 909 AN: 41532

American (AMR) AF: 0.0530 AC: 811 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 360 AN: 3468

East Asian (EAS) AF: 0.0835 AC: 433 AN: 5184

South Asian (SAS) AF: 0.114 AC: 547 AN: 4818

European-Finnish (FIN) AF: 0.0587 AC: 621 AN: 10584

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0693 AC: 4714 AN: 68000

Other (OTH) AF: 0.0602 AC: 127 AN: 2110

Alfa AF: 0.0511 Hom.: 61

Bravo AF: 0.0529

Asia WGS AF: 0.0900 AC: 315 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.5
DANN	Benign	0.63
PhyloP100		-0.036
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs41282721; hg19: chr7-140500135; COSMIC: COSV56078567;