ENST00000471181.7:c.4405C>A

Variant names:

• chr17-43079352-G-T
• rs1555583238
• ENST00000471181.7:c.4405C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000471181.7(BRCA1):​c.4405C>A​(p.Pro1469Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1469S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BRCA1 ENST00000471181.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.01
• Publications: 0 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]

RPL21P4 (HGNC:17959): (ribosomal protein L21 pseudogene 4)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15677488).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000471181.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.4358-2738C>A		intron	N/A	NP_009225.1
	BRCA1	NM_001407581.1		c.4405C>A	p.Pro1469Thr	missense	Exon 13 of 24	NP_001394510.1
	BRCA1	NM_001407582.1		c.4405C>A	p.Pro1469Thr	missense	Exon 13 of 24	NP_001394511.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000471181.7	TSL:1	c.4405C>A	p.Pro1469Thr	missense	Exon 13 of 24	ENSP00000418960.2
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.4358-2738C>A		intron	N/A	ENSP00000350283.3
	BRCA1	ENST00000470026.6	TSL:1	c.4358-2738C>A		intron	N/A	ENSP00000419274.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.92e-7 AC: 1 AN: 1444452 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 719048

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5252

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110636

Other (OTH) AF: 0.00 AC: 0 AN: 60200

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.0030	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	9.8
DANN	Benign	0.84
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.61	T
PhyloP100		4.0
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.043	D
Vest4		0.39
MutPred		0.16		Gain of phosphorylation at P1469 (P = 0.0213)
MVP		0.72
MPC		0.091
ClinPred		0.37	T
GERP RS		0.36
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs1555583238; hg19: chr17-41231369;