rs1546585

Positions:

• chr17-43144609-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001408458.1(BRCA1):​c.-62+25517A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0982 in 166,114 control chromosomes in the GnomAD database, including 2,668 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (2661 hom., cov: 32)
  • Exomes 𝑓: 0.011 (7 hom.)
• Consequence: BRCA1 NM_001408458.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.385

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:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_001408458.1	c.-62+25517A>T		intron_variant			NP_001395387.1
NBR2	NR_003108.2	n.1012-119T>A		intron_variant
NBR2	NR_138145.1	n.1175+2033T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000634433.2	c.-19-20494A>T		intron_variant		5		ENSP00000489431.2
NBR2	ENST00000460115.5	n.959-119T>A		intron_variant		2
NBR2	ENST00000467245.5	n.1088+2033T>A		intron_variant		2
NBR2	ENST00000657841.1	n.1847+4326T>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16107 AN: 152136 Hom.: 2641 Cov.: 32

Gnomad AFR AF: 0.352

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0380

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0292

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.00885

Gnomad OTH AF: 0.0750

GnomAD4 exome AF: 0.0107 AC: 148 AN: 13860 Hom.: 7 AF XY: 0.0122 AC XY: 91 AN XY: 7458

Gnomad4 AFR exome AF: 0.304

Gnomad4 AMR exome AF: 0.0204

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0254

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00588

Gnomad4 OTH exome AF: 0.0239

GnomAD4 genome AF: 0.106 AC: 16170 AN: 152254 Hom.: 2661 Cov.: 32 AF XY: 0.103 AC XY: 7656 AN XY: 74458

Gnomad4 AFR AF: 0.353

Gnomad4 AMR AF: 0.0378

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0286

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00885

Gnomad4 OTH AF: 0.0742

Alfa AF: 0.0661 Hom.: 203

Bravo AF: 0.120

Asia WGS AF: 0.0410 AC: 143 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.8
DANN	Benign	0.78

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1546585; hg19: chr17-41296626;