17-61859888-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032043.3(BRIP1):​c.113G>A​(p.Ser38Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S38G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.471
Variant links:
Genes affected
BRIP1 (HGNC:20473): (BRCA1 interacting helicase 1) The protein encoded by this gene is a member of the RecQ DEAH helicase family and interacts with the BRCT repeats of breast cancer, type 1 (BRCA1). The bound complex is important in the normal double-strand break repair function of breast cancer, type 1 (BRCA1). This gene may be a target of germline cancer-inducing mutations. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.08520505).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRIP1NM_032043.3 linkc.113G>A p.Ser38Asn missense_variant Exon 3 of 20 ENST00000259008.7 NP_114432.2 Q9BX63-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRIP1ENST00000259008.7 linkc.113G>A p.Ser38Asn missense_variant Exon 3 of 20 1 NM_032043.3 ENSP00000259008.2 Q9BX63-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1459730
Hom.:
0
Cov.:
29
AF XY:
0.00000138
AC XY:
1
AN XY:
726378
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.01e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
Jan 23, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRIP1 protein function. ClinVar contains an entry for this variant (Variation ID: 483153). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 38 of the BRIP1 protein (p.Ser38Asn). -

Hereditary cancer-predisposing syndrome Uncertain:1
Nov 05, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.S38N variant (also known as c.113G>A), located in coding exon 2 of the BRIP1 gene, results from a G to A substitution at nucleotide position 113. The serine at codon 38 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.084
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.58
CADD
Benign
17
DANN
Benign
0.89
DEOGEN2
Benign
0.077
T;.;.
Eigen
Benign
-0.34
Eigen_PC
Benign
-0.14
FATHMM_MKL
Benign
0.67
D
LIST_S2
Benign
0.76
T;T;T
M_CAP
Benign
0.0079
T
MetaRNN
Benign
0.085
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.20
N;N;.
PrimateAI
Uncertain
0.48
T
PROVEAN
Benign
-0.19
N;.;.
REVEL
Benign
0.045
Sift
Benign
0.41
T;.;.
Sift4G
Benign
0.57
T;T;.
Polyphen
0.039
B;.;.
Vest4
0.22
MutPred
0.31
Loss of catalytic residue at K39 (P = 0.066);Loss of catalytic residue at K39 (P = 0.066);Loss of catalytic residue at K39 (P = 0.066);
MVP
0.47
MPC
0.15
ClinPred
0.13
T
GERP RS
4.6
Varity_R
0.034
gMVP
0.33

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555618429; hg19: chr17-59937249; API