rs71645935

Variant names:

• chr7-140924722-G-A
• rs71645935
• NM_001374258.1:c.-19C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001374258.1(BRAF):​c.-19C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00285 in 845,450 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (31 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (17 hom.)
• Consequence: BRAF NM_001374258.1 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.171
• 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: 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=-0.73).
• BP6: Variant 7-140924722-G-A is Benign according to our data. Variant chr7-140924722-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0105 (1591/151548) while in subpopulation AFR AF = 0.0356 (1475/41378). AF 95% confidence interval is 0.0341. There are 31 homozygotes in GnomAd4. There are 703 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1591 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	NM_001374258.1	MANE Plus Clinical	c.-19C>T		5_prime_UTR	Exon 1 of 20	NP_001361187.1
	BRAF	NM_004333.6	MANE Select	c.-19C>T		5_prime_UTR	Exon 1 of 18	NP_004324.2
	BRAF	NM_001374244.1		c.-19C>T		5_prime_UTR	Exon 1 of 19	NP_001361173.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	ENST00000644969.2	MANE Plus Clinical	c.-19C>T		5_prime_UTR	Exon 1 of 20	ENSP00000496776.1
	BRAF	ENST00000646891.2	MANE Select	c.-19C>T		5_prime_UTR	Exon 1 of 18	ENSP00000493543.1
	BRAF	ENST00000288602.11	TSL:1	c.-19C>T		5_prime_UTR	Exon 1 of 19	ENSP00000288602.7

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1584 AN: 151442 Hom.: 31 Cov.: 31

Gnomad AFR AF: 0.0356

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00558

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00114 AC: 98 AN: 86066 AF XY: 0.000900

Gnomad AFR exome AF: 0.0427

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000192

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00118 AC: 821 AN: 693902 Hom.: 17 Cov.: 9 AF XY: 0.00103 AC XY: 375 AN XY: 364762

African (AFR) AF: 0.0399 AC: 581 AN: 14566

American (AMR) AF: 0.00314 AC: 89 AN: 28316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19496

East Asian (EAS) AF: 0.00 AC: 0 AN: 26900

South Asian (SAS) AF: 0.000163 AC: 10 AN: 61214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32744

Middle Eastern (MID) AF: 0.00222 AC: 6 AN: 2702

European-Non Finnish (NFE) AF: 0.0000676 AC: 32 AN: 473652

Other (OTH) AF: 0.00300 AC: 103 AN: 34312

GnomAD4 genome AF: 0.0105 AC: 1591 AN: 151548 Hom.: 31 Cov.: 31 AF XY: 0.00950 AC XY: 703 AN XY: 74032

African (AFR) AF: 0.0356 AC: 1475 AN: 41378

American (AMR) AF: 0.00558 AC: 85 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10468

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67758

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00560 Hom.: 3

Bravo AF: 0.0120

Asia WGS AF: 0.00319 AC: 11 AN: 3460

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	LEOPARD syndrome 3 (1)
-	-	1	Noonan syndrome 7 (1)
-	-	1	not provided (1)
-	-	1	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	17
DANN	Benign	0.85
PhyloP100		0.17
PromoterAI		-0.0043	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	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: rs71645935; hg19: chr7-140624522;