17-43044804-CTTTTTTTTTTT-CTTTTTTT

Variant names:

• chr17-43044804-CTTTT-C
• rs59541324
• ENST00000468300.5:c.*976_*979delAAAA

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

The ENST00000468300.5(BRCA1):​c.*976_*979delAAAA variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00765 in 368,452 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 0.000058 (0 hom., cov: 0)
  • Exomes 𝑓: 0.011 (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 Likely_benign. Variant got -4 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0114 (2810/247058) while in subpopulation EAS AF= 0.0172 (202/11758). AF 95% confidence interval is 0.0152. There are 0 homozygotes in gnomad4_exome. There are 1636 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.*870_*873delAAAA		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.*870_*873delAAAA		3_prime_UTR_variant	Exon 23 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.0000577 AC: 7 AN: 121382 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000327

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000386

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000676

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0337 AC: 1666 AN: 49390 Hom.: 0 AF XY: 0.0347 AC XY: 942 AN XY: 27116

Gnomad AFR exome AF: 0.0180

Gnomad AMR exome AF: 0.0259

Gnomad ASJ exome AF: 0.0451

Gnomad EAS exome AF: 0.0330

Gnomad SAS exome AF: 0.0506

Gnomad FIN exome AF: 0.0455

Gnomad NFE exome AF: 0.0311

Gnomad OTH exome AF: 0.0256

GnomAD4 exome AF: 0.0114 AC: 2810 AN: 247058 Hom.: 0 AF XY: 0.0117 AC XY: 1636 AN XY: 140132

Gnomad4 AFR exome AF: 0.00745

Gnomad4 AMR exome AF: 0.0126

Gnomad4 ASJ exome AF: 0.0244

Gnomad4 EAS exome AF: 0.0172

Gnomad4 SAS exome AF: 0.0112

Gnomad4 FIN exome AF: 0.00862

Gnomad4 NFE exome AF: 0.0103

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.0000577 AC: 7 AN: 121394 Hom.: 0 Cov.: 0 AF XY: 0.0000523 AC XY: 3 AN XY: 57348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000327

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000386

Gnomad4 NFE AF: 0.0000676

Gnomad4 OTH AF: 0.00

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;