17-43104150-A-T

Variant names:

• chr17-43104150-A-T
• NM_007294.4:c.413T>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007294.4(BRCA1):​c.413T>A​(p.Leu138Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0750

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13455722).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.413T>A	p.Leu138Gln	missense_variant	Exon 6 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.413T>A	p.Leu138Gln	missense_variant	Exon 6 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	12
DANN	Benign	0.88
DEOGEN2	Benign	0.082	.;T;.;.;.;.;.;T;.;T;.;T;T;.;T;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.81	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N;N;.;N;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.77	N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;N
REVEL	Uncertain	0.54
Sift	Benign	0.43	T;T;T;T;T;T;T;T;T;T;T;.;T;T;T;T
Sift4G	Benign	0.36	T;T;T;T;T;T;.;.;T;.;T;.;T;.;T;.
Polyphen		0.20, 0.43, 0.45, 0.0	.;B;.;.;.;B;.;P;.;.;B;.;.;.;.;.
Vest4		0.17
MutPred		0.28		Gain of ubiquitination at K135 (P = 0.0462);Gain of ubiquitination at K135 (P = 0.0462);Gain of ubiquitination at K135 (P = 0.0462);Gain of ubiquitination at K135 (P = 0.0462);.;Gain of ubiquitination at K135 (P = 0.0462);.;Gain of ubiquitination at K135 (P = 0.0462);.;.;Gain of ubiquitination at K135 (P = 0.0462);Gain of ubiquitination at K135 (P = 0.0462);Gain of ubiquitination at K135 (P = 0.0462);.;Gain of ubiquitination at K135 (P = 0.0462);Gain of ubiquitination at K135 (P = 0.0462);
MVP		0.62
MPC		0.085
ClinPred		0.26	T
GERP RS		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.093
gMVP		0.29

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-41256167;