chr17-43169893-C-T

Variant names:

• chr17-43169893-C-T
• rs9908805
• ENST00000590740.2:n.278+233G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001408458.1(BRCA1):​c.-62+233G>A variant causes a intron 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: BRCA1 NM_001408458.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.318
• Publications: 5 publications found

Genes affected

ENSG00000267002 (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]

BRCA1P1 (HGNC:28470): (BRCA1 pseudogene 1)

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001408458.1. 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_001408458.1		c.-62+233G>A		intron	N/A	NP_001395387.1	B4DES0
	LOC101929767	NR_110868.1		n.278+233G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000267002	ENST00000590740.2	TSL:1	n.278+233G>A		intron	N/A
	BRCA1	ENST00000634433.2	TSL:5	c.-20+233G>A		intron	N/A	ENSP00000489431.2	A0A0U1RRA9
	ENSG00000267340	ENST00000589047.1	TSL:6	n.185G>A		non_coding_transcript_exon	Exon 1 of 1

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

African (AFR) AF: 0.649 AC: 4473 AN: 6894

American (AMR) AF: 0.980 AC: 23440 AN: 23910

Ashkenazi Jewish (ASJ) AF: 0.995 AC: 5997 AN: 6028

East Asian (EAS) AF: 1.00 AC: 9897 AN: 9898

South Asian (SAS) AF: 0.973 AC: 48627 AN: 50000

European-Finnish (FIN) AF: 0.999 AC: 18768 AN: 18794

Middle Eastern (MID) AF: 0.955 AC: 770 AN: 806

European-Non Finnish (NFE) AF: 0.992 AC: 145405 AN: 146582

Other (OTH) AF: 0.973 AC: 11970 AN: 12306

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

African (AFR) AF: 0.648 AC: 26867 AN: 41468

American (AMR) AF: 0.962 AC: 14721 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.995 AC: 3451 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5168 AN: 5168

South Asian (SAS) AF: 0.971 AC: 4683 AN: 4822

European-Finnish (FIN) AF: 0.998 AC: 10588 AN: 10604

Middle Eastern (MID) AF: 0.939 AC: 276 AN: 294

European-Non Finnish (NFE) AF: 0.991 AC: 67414 AN: 68022

Other (OTH) AF: 0.926 AC: 1957 AN: 2114

Alfa AF: 0.958 Hom.: 172676

Bravo AF: 0.880

Asia WGS AF: 0.959 AC: 3335 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.1
DANN	Benign	0.52
PhyloP100		0.32
PromoterAI		-0.0090	Neutral

Splicing

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

Other links and lift over

dbSNP: rs9908805; hg19: chr17-41321910;