17-43044804-CTTTTTTTTTTT-CTTTTTTTT

Variant names:

• chr17-43044804-CTTT-C
• rs59541324
• ENST00000468300.5:c.*977_*979delAAA

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The ENST00000468300.5(BRCA1):​c.*977_*979delAAA variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0421 in 357,632 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00073 (0 hom., cov: 0)
  • Exomes 𝑓: 0.063 (0 hom.)
• Consequence: BRCA1 ENST00000468300.5 splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.446

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0843 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.*871_*873delAAA		3_prime_UTR_variant	Exon 23 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654	c.*871_*873delAAA		3_prime_UTR_variant	Exon 23 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.000733 AC: 89 AN: 121364 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000603

Gnomad ASJ AF: 0.000327

Gnomad EAS AF: 0.000451

Gnomad SAS AF: 0.000278

Gnomad FIN AF: 0.00521

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.00183

GnomAD3 exomes AF: 0.112 AC: 5543 AN: 49390 Hom.: 0 AF XY: 0.116 AC XY: 3143 AN XY: 27116

Gnomad AFR exome AF: 0.0736

Gnomad AMR exome AF: 0.0867

Gnomad ASJ exome AF: 0.126

Gnomad EAS exome AF: 0.116

Gnomad SAS exome AF: 0.159

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.0633 AC: 14960 AN: 236256 Hom.: 0 AF XY: 0.0657 AC XY: 8823 AN XY: 134322

Gnomad4 AFR exome AF: 0.0425

Gnomad4 AMR exome AF: 0.0497

Gnomad4 ASJ exome AF: 0.0820

Gnomad4 EAS exome AF: 0.0688

Gnomad4 SAS exome AF: 0.0866

Gnomad4 FIN exome AF: 0.0631

Gnomad4 NFE exome AF: 0.0564

Gnomad4 OTH exome AF: 0.0624

GnomAD4 genome AF: 0.000733 AC: 89 AN: 121376 Hom.: 0 Cov.: 0 AF XY: 0.000942 AC XY: 54 AN XY: 57338

Gnomad4 AFR AF: 0.000253

Gnomad4 AMR AF: 0.000602

Gnomad4 ASJ AF: 0.000327

Gnomad4 EAS AF: 0.000453

Gnomad4 SAS AF: 0.000279

Gnomad4 FIN AF: 0.00521

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.00182

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs59541324; hg19: chr17-41196821;