chr7-140778059-T-C

Variant names:

• chr7-140778059-T-C
• rs727504375
• NM_001374258.1:c.1569A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 4P and 3B. PM2 PP3_Moderate BP6_Moderate BP7

The NM_001374258.1(BRAF):​c.1569A>G​(p.Lys523Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_001374258.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.710
• Publications: 0 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

ENSG00000289788 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: REVEL computational evidence supports a deleterious effect, 0.905
• BP6: Variant 7-140778059-T-C is Benign according to our data. Variant chr7-140778059-T-C is described in CliVar as Likely_benign. Clinvar id is 1772851.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-140778059-T-C is described in CliVar as Likely_benign. Clinvar id is 1772851.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-140778059-T-C is described in CliVar as Likely_benign. Clinvar id is 1772851.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-140778059-T-C is described in CliVar as Likely_benign. Clinvar id is 1772851.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-140778059-T-C is described in CliVar as Likely_benign. Clinvar id is 1772851.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-140778059-T-C is described in CliVar as Likely_benign. Clinvar id is 1772851.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-140778059-T-C is described in CliVar as Likely_benign. Clinvar id is 1772851.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-140778059-T-C is described in CliVar as Likely_benign. Clinvar id is 1772851.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-140778059-T-C is described in CliVar as Likely_benign. Clinvar id is 1772851.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-140778059-T-C is described in CliVar as Likely_benign. Clinvar id is 1772851.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-140778059-T-C is described in CliVar as Likely_benign. Clinvar id is 1772851.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-140778059-T-C is described in CliVar as Likely_benign. Clinvar id is 1772851.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-140778059-T-C is described in CliVar as Likely_benign. Clinvar id is 1772851.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-140778059-T-C is described in CliVar as Likely_benign. Clinvar id is 1772851.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-140778059-T-C is described in CliVar as Likely_benign. Clinvar id is 1772851.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-140778059-T-C is described in CliVar as Likely_benign. Clinvar id is 1772851.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-140778059-T-C is described in CliVar as Likely_benign. Clinvar id is 1772851.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-140778059-T-C is described in CliVar as Likely_benign. Clinvar id is 1772851.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-140778059-T-C is described in CliVar as Likely_benign. Clinvar id is 1772851.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-140778059-T-C is described in CliVar as Likely_benign. Clinvar id is 1772851.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-140778059-T-C is described in CliVar as Likely_benign. Clinvar id is 1772851.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-140778059-T-C is described in CliVar as Likely_benign. Clinvar id is 1772851.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-140778059-T-C is described in CliVar as Likely_benign. Clinvar id is 1772851.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.71 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.1569A>G	p.Lys523Lys	synonymous_variant	Exon 13 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1449A>G	p.Lys483Lys	synonymous_variant	Exon 12 of 18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.1569A>G	p.Lys523Lys	synonymous_variant	Exon 13 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1449A>G	p.Lys483Lys	synonymous_variant	Exon 12 of 18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Benign:1

Nov 16, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	6.0
DANN	Benign	0.65
PhyloP100		0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs727504375; hg19: chr7-140477859;