17-43169893-C-T

Position:

• chr17-43169893-C-T

Variant summary

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

The ENST00000589047.1(ENSG00000267340):​n.185G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.949 in 427,392 control chromosomes in the GnomAD database, including 194,854 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 0.89 (62594 hom., cov: 31)
  • Exomes 𝑓: 0.98 (132260 hom.)
• Consequence: ENST00000589047.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.318

Genes affected

(HGNC:):

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.985 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOC101929767	NR_110868.1	n.278+233G>A		intron_variant, non_coding_transcript_variant
LOC124900391	XR_007065760.1	n.549+523G>A		intron_variant, non_coding_transcript_variant
BRCA1	NM_001408458.1	c.-62+233G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
	ENST00000589047.1	n.185G>A		non_coding_transcript_exon_variant	1/1
	ENST00000635600.1	n.191+233G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.894 AC: 135982 AN: 152056 Hom.: 62579 Cov.: 31

Gnomad AFR AF: 0.649

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.962

Gnomad ASJ AF: 0.995

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.971

Gnomad FIN AF: 0.998

Gnomad MID AF: 0.934

Gnomad NFE AF: 0.991

Gnomad OTH AF: 0.925

GnomAD4 exome AF: 0.979 AC: 269347 AN: 275218 Hom.: 132260 Cov.: 0 AF XY: 0.980 AC XY: 155731 AN XY: 158950

Gnomad4 AFR exome AF: 0.649

Gnomad4 AMR exome AF: 0.980

Gnomad4 ASJ exome AF: 0.995

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.973

Gnomad4 FIN exome AF: 0.999

Gnomad4 NFE exome AF: 0.992

Gnomad4 OTH exome AF: 0.973

GnomAD4 genome AF: 0.894 AC: 136037 AN: 152174 Hom.: 62594 Cov.: 31 AF XY: 0.897 AC XY: 66758 AN XY: 74392

Gnomad4 AFR AF: 0.648

Gnomad4 AMR AF: 0.962

Gnomad4 ASJ AF: 0.995

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.971

Gnomad4 FIN AF: 0.998

Gnomad4 NFE AF: 0.991

Gnomad4 OTH AF: 0.926

Alfa AF: 0.979 Hom.: 113945

Bravo AF: 0.880

Asia WGS AF: 0.959 AC: 3335 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.1
DANN	Benign	0.52

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs9908805; hg19: chr17-41321910;