rs587782679

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000259008.7(BRIP1):ā€‹c.2902A>Gā€‹(p.Lys968Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000274 in 1,607,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K968K) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 33)
Exomes š‘“: 0.000029 ( 0 hom. )

Consequence

BRIP1
ENST00000259008.7 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 0.281
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 Likely_benign. Variant got -4 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0671843).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRIP1NM_032043.3 linkuse as main transcriptc.2902A>G p.Lys968Glu missense_variant 19/20 ENST00000259008.7 NP_114432.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRIP1ENST00000259008.7 linkuse as main transcriptc.2902A>G p.Lys968Glu missense_variant 19/201 NM_032043.3 ENSP00000259008 P2Q9BX63-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152216
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000160
AC:
4
AN:
249428
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135026
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000354
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000289
AC:
42
AN:
1454972
Hom.:
0
Cov.:
30
AF XY:
0.0000345
AC XY:
25
AN XY:
724230
show subpopulations
Gnomad4 AFR exome
AF:
0.0000301
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:
0.0000343
Gnomad4 OTH exome
AF:
0.0000499
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152216
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74380
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000283
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthOct 31, 2016- -
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 27, 2023The p.K968E variant (also known as c.2902A>G), located in coding exon 18 of the BRIP1 gene, results from an A to G substitution at nucleotide position 2902. The lysine at codon 968 is replaced by glutamic acid, an amino acid with 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. -
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Nov 01, 2021- -
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsJul 14, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 08, 2023This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 968 of the BRIP1 protein (p.Lys968Glu). This variant is present in population databases (rs587782679, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 142732). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.064
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
14
DANN
Benign
0.97
DEOGEN2
Benign
0.10
T;.
Eigen
Benign
-0.84
Eigen_PC
Benign
-0.76
FATHMM_MKL
Benign
0.050
N
LIST_S2
Benign
0.29
T;T
M_CAP
Benign
0.029
D
MetaRNN
Benign
0.067
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.1
L;L
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-0.33
N;.
REVEL
Benign
0.033
Sift
Benign
0.11
T;.
Sift4G
Benign
0.48
T;T
Polyphen
0.0
B;.
Vest4
0.16
MutPred
0.26
Loss of ubiquitination at K968 (P = 0.002);Loss of ubiquitination at K968 (P = 0.002);
MVP
0.64
MPC
0.23
ClinPred
0.030
T
GERP RS
1.8
Varity_R
0.063
gMVP
0.19

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
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: rs587782679; hg19: chr17-59763200; API