NM_007294.4:c.124A>T

Variant names:

• chr17-43115736-T-A
• rs80357163
• NM_007294.4:c.124A>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_007294.4(BRCA1):​c.124A>T​(p.Ile42Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 2.14

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a zinc_finger_region RING-type (size 41) in uniprot entity BRCA1_HUMAN there are 65 pathogenic changes around while only 6 benign (92%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.124A>T	p.Ile42Leu	missense_variant	Exon 3 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.124A>T	p.Ile42Leu	missense_variant	Exon 3 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Other:1

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Brotman Baty Institute, University of Washington

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	.;T;.;.;.;T;.;T;T;.;T;T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;T;D;D;T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	0.10	N;N;N;N;N;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.28	N;N;N;N;N;N;N;.;N;N;N;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.16	T;D;D;T;D;T;D;.;D;D;D;T;T
Sift4G	Benign	0.52	T;D;D;T;T;.;D;.;D;.;D;.;.
Polyphen		0.90, 0.56, 0.94	.;P;.;.;P;.;P;.;.;.;.;.;.
Vest4		0.60
MutPred		0.53		Loss of catalytic residue at I42 (P = 0.1167);Loss of catalytic residue at I42 (P = 0.1167);Loss of catalytic residue at I42 (P = 0.1167);Loss of catalytic residue at I42 (P = 0.1167);Loss of catalytic residue at I42 (P = 0.1167);Loss of catalytic residue at I42 (P = 0.1167);Loss of catalytic residue at I42 (P = 0.1167);Loss of catalytic residue at I42 (P = 0.1167);Loss of catalytic residue at I42 (P = 0.1167);Loss of catalytic residue at I42 (P = 0.1167);Loss of catalytic residue at I42 (P = 0.1167);Loss of catalytic residue at I42 (P = 0.1167);Loss of catalytic residue at I42 (P = 0.1167);
MVP		0.94
MPC		0.28
ClinPred		0.67	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs80357163; hg19: chr17-41267753;