rs8176304

Variant names:

• chr17-43049415-G-T
• rs8176304
• NM_007294.4:c.5333-221C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-43049415-G-T
• chr17-43049415-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007294.4(BRCA1):​c.5333-221C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00439 in 152,104 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.0044 (6 hom., cov: 31)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel B:4
• Conservation: PhyloP100: 0.707
• Publications: 3 publications found

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]

BRCA1 Gene-Disease associations (from GenCC):

• BRCA1-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for BRCA1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-43049415-G-T is Benign according to our data. Variant chr17-43049415-G-T is described in ClinVar as Benign. ClinVar VariationId is 209249.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00439 (668/152104) while in subpopulation AFR AF = 0.0149 (616/41468). AF 95% confidence interval is 0.0139. There are 6 homozygotes in GnomAd4. There are 332 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007294.4. 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_007294.4	MANE Select	c.5333-221C>A		intron	N/A	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5399-221C>A		intron	N/A	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5399-221C>A		intron	N/A	NP_001394511.1	A0A2R8Y7V5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.5333-221C>A		intron	N/A	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5396-221C>A		intron	N/A	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5333-221C>A		intron	N/A	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.00439 AC: 667 AN: 151986 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00256

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00528

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00439 AC: 668 AN: 152104 Hom.: 6 Cov.: 31 AF XY: 0.00446 AC XY: 332 AN XY: 74358

African (AFR) AF: 0.0149 AC: 616 AN: 41468

American (AMR) AF: 0.00255 AC: 39 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.00522 AC: 11 AN: 2106

Alfa AF: 0.00320 Hom.: 2

Bravo AF: 0.00515

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Breast-ovarian cancer, familial, susceptibility to, 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.0
DANN	Benign	0.65
PhyloP100		0.71
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs8176304; hg19: chr17-41201432;