chr17-43125337-G-A

Variant names:

• chr17-43125337-G-A
• rs143160357
• NM_007294.4:c.-86C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_007294.4(BRCA1):​c.-86C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000818 in 445,956 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00079 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (1 hom.)
• Consequence: BRCA1 NM_007294.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: -0.243
• Publications: 5 publications found

Genes affected

BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

NBR2 (HGNC:20691): (neighbor of BRCA1 lncRNA 2) This gene was identified by its close proximity on chromosome 17 to tumor suppressor gene BRCA1. Experimental evidence indicates that the two genes share a bi-directional promoter. Transcription for either gene is controlled individually by distinct transcriptional repressor factors. A short (112 amino acid) open reading frame is observed which includes a region derived from a LINE1 element. A strong Kozak signal is not observed for the putative ORF and the stop codon is more than 55 nucleotides upstream of the last splice site for the transcript, suggesting that the transcript is subject to nonsense-mediated decay. Therefore, this gene does not appear to encode a protein. Glucose starvation induces the expression of this gene and the long non-coding RNA transcribed by it functions with AMP-activated protein kinase in mediating the energy stress response. [provided by RefSeq, Aug 2016]

ACMG classification

Specifications for BRCA1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-43125337-G-A is Benign according to our data. Variant chr17-43125337-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 323423.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007294.4. 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
	BRCA1	NM_007294.4	MANE Select	c.-86C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 23	NP_009225.1	P38398-1
	BRCA1	NM_007294.4	MANE Select	c.-86C>T		5_prime_UTR	Exon 1 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.-86C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 24	NP_001394510.1	A0A2R8Y7V5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.-86C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.-86C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.-175C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.000788 AC: 120 AN: 152204 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000847 AC: 109 AN: 128622 AF XY: 0.000840

Gnomad AFR exome AF: 0.000165

Gnomad AMR exome AF: 0.00227

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000374

Gnomad NFE exome AF: 0.000754

Gnomad OTH exome AF: 0.00127

GnomAD4 exome AF: 0.000834 AC: 245 AN: 293634 Hom.: 1 Cov.: 0 AF XY: 0.000887 AC XY: 147 AN XY: 165678

African (AFR) AF: 0.000119 AC: 1 AN: 8388

American (AMR) AF: 0.00213 AC: 57 AN: 26786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10564

East Asian (EAS) AF: 0.00 AC: 0 AN: 8892

South Asian (SAS) AF: 0.000706 AC: 42 AN: 59460

European-Finnish (FIN) AF: 0.000162 AC: 2 AN: 12310

Middle Eastern (MID) AF: 0.00344 AC: 9 AN: 2616

European-Non Finnish (NFE) AF: 0.000822 AC: 124 AN: 150940

Other (OTH) AF: 0.000731 AC: 10 AN: 13678

GnomAD4 genome AF: 0.000788 AC: 120 AN: 152322 Hom.: 2 Cov.: 32 AF XY: 0.000967 AC XY: 72 AN XY: 74476

African (AFR) AF: 0.0000481 AC: 2 AN: 41580

American (AMR) AF: 0.00301 AC: 46 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000941 AC: 64 AN: 68030

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000634 Hom.: 0

Bravo AF: 0.000842

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Breast and/or ovarian cancer (1)
-	1	-	Breast-ovarian cancer, familial, susceptibility to, 1 (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	1	-	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.5
DANN	Benign	0.85
PhyloP100		-0.24
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=282/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs143160357; hg19: chr17-41277354;