7-140924663-G-T

Variant names:

• chr7-140924663-G-T
• rs397507455
• NM_001374258.1:c.41C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_004333.6(BRAF):​c.41C>A​(p.Pro14Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000831 in 1,203,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P14L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: BRAF NM_004333.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.220
• 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: 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the BRAF gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 139 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. Gene score misZ: 3.7208 (above the threshold of 3.09). Trascript score misZ: 4.9447 (above the threshold of 3.09). GenCC associations: The gene is linked to LEOPARD syndrome 3, Costello syndrome, Noonan syndrome 7, Noonan syndrome-like disorder with loose anagen hair, cardiofaciocutaneous syndrome 1, cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, Noonan syndrome, anaplastic astrocytoma.
• BP4: Computational evidence support a benign effect (MetaRNN=0.09245515).

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.41C>A	p.Pro14Gln	missense	Exon 1 of 20	NP_001361187.1	A0A2R8Y8E0
	BRAF	NM_004333.6	MANE Select	c.41C>A	p.Pro14Gln	missense	Exon 1 of 18	NP_004324.2
	BRAF	NM_001374244.1		c.41C>A	p.Pro14Gln	missense	Exon 1 of 19	NP_001361173.1	A0A2U3TZI2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	ENST00000644969.2	MANE Plus Clinical	c.41C>A	p.Pro14Gln	missense	Exon 1 of 20	ENSP00000496776.1	A0A2R8Y8E0
	BRAF	ENST00000646891.2	MANE Select	c.41C>A	p.Pro14Gln	missense	Exon 1 of 18	ENSP00000493543.1	P15056
	BRAF	ENST00000288602.11	TSL:1	c.41C>A	p.Pro14Gln	missense	Exon 1 of 19	ENSP00000288602.7	A0A2U3TZI2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.31e-7 AC: 1 AN: 1203408 Hom.: 0 Cov.: 17 AF XY: 0.00000166 AC XY: 1 AN XY: 601312

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

African (AFR) AF: 0.00 AC: 0 AN: 24930

American (AMR) AF: 0.00 AC: 0 AN: 33292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23304

East Asian (EAS) AF: 0.00 AC: 0 AN: 32268

South Asian (SAS) AF: 0.00 AC: 0 AN: 74096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33212

Middle Eastern (MID) AF: 0.000266 AC: 1 AN: 3762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 926996

Other (OTH) AF: 0.00 AC: 0 AN: 51548

⚠️ 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 Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Benign	0.81
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.22
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.14
Sift	Benign	0.41	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.26
MutPred		0.090		Gain of helix (P = 0.0854)
MVP		0.38
MPC		0.88
ClinPred		0.074	T
GERP RS		2.0
PromoterAI		0.057	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.034
gMVP		0.081
Mutation Taster		=93/7	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: rs397507455; hg19: chr7-140624463;