7-140924722-G-A

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_004333.6(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_004333.6 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.171

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]

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 [Likely_benign]. Clinvar id 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 FAILED quality control check.
• BS2: High AC in GnomAd4 at 1591 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.-19C>T		5_prime_UTR_variant	Exon 1 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.-19C>T		5_prime_UTR_variant	Exon 1 of 18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.-19C>T		5_prime_UTR_variant	Exon 1 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.-19C>T		5_prime_UTR_variant	Exon 1 of 18		NM_004333.6	ENSP00000493543.1

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

Gnomad4 AFR exome AF: 0.0399 AC: 581 AN: 14566

Gnomad4 AMR exome AF: 0.00314 AC: 89 AN: 28316

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 19496

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 26900

Gnomad4 SAS exome AF: 0.000163 AC: 10 AN: 61214

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 32744

Gnomad4 NFE exome AF: 0.0000676 AC: 32 AN: 473652

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.0356 AC: 0.035647 AN: 0.035647

Gnomad4 AMR AF: 0.00558 AC: 0.00557596 AN: 0.00557596

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000208 AC: 0.000207987 AN: 0.000207987

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000162 AC: 0.000162342 AN: 0.000162342

Gnomad4 OTH AF: 0.00851 AC: 0.00851466 AN: 0.00851466

Alfa AF: 0.00560 Hom.: 3

Bravo AF: 0.0120

Asia WGS AF: 0.00319 AC: 11 AN: 3460

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Jan 15, 2015

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 18, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 25, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRAF c.-19C>T is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.0011 in 86066 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 455-folds over the estimated maximal expected allele frequency for a pathogenic variant in BRAF causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. Two ClinVar submissions (evaluation after 2014) cites the variant once as likely benign and once as benign. Based on the evidence outlined above, the variant was classified as benign. -

Jun 01, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

-19C>T in the 5'UTR of BRAF: This variant has been reported in dbSNP in 2.3% (1/ 44) Hispanic chromosomes and 4.2% (1/24) Black chromosomes (rs71645935). This va riant is located in the 5'UTR and variants in regulatory regions could have an e ffect on transcriptional or translational efficiency. However, no variants in th is region of BRAF have been found to be pathogenic in individuals with Noonan sp ectrum disorders.Therefore, this variant is not expected to have clinical signif icance. -

Noonan syndrome 7 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Nov 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LEOPARD syndrome 3 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

RASopathy Benign:1

Mar 02, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is found in NOONAN panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	17
DANN	Benign	0.85
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

Publications

LitVar

Other links and lift over

dbSNP: rs71645935; hg19: chr7-140624522;