rs45566938

Positions:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BP7

The NM_032043.3(BRIP1):c.36G>T(p.Gly12Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00026 in 1,613,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:13

Conservation

PhyloP100: 0.206

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]

BRIP1 links:

BRIP1 (HGNC:):

BRIP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 17-61861504-C-A is Benign according to our data. Variant chr17-61861504-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 136582.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=1, Benign=5}. Variant chr17-61861504-C-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.206 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRIP1	NM_032043.3 linkuse as main transcript	c.36G>T	p.Gly12Gly	synonymous_variant	2/20	ENST00000259008.7	NP_114432.2	Q9BX63-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7 linkuse as main transcript	c.36G>T	p.Gly12Gly	synonymous_variant	2/20	1	NM_032043.3	ENSP00000259008.2		Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.000178

AC:

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.000338

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000239

AC:

AN:

251306

Hom.:

AF XY:

0.000272

AC XY:

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

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:

0.000466

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000269

AC:

393

AN:

1461020

Hom.:

Cov.:

AF XY:

0.000268

AC XY:

195

AN XY:

726886

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000331

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000178

AC:

AN:

152006

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.000219

EpiCase

AF:

0.000709

EpiControl

AF:

0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 09, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 03, 2014	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 04, 2015	- -

Fanconi anemia complementation group J

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Oct 26, 2016	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	BRIP1: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 16, 2017	Variant summary: The BRIP1 c.36G>T (p.Gly12Gly) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. The variant lies within a P-loop domain, a helicase domain, a helicase-like DEXD box domain, and a helicase superfamily ATP-binding domain of the protein (InterPro), though none of these domains are listed in the NCBI Conserved Domain database at the variant location. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant does not signifcantly affect ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExAC in 31/121030 control chromosomes, exclusively observed in the European (Non-Finnish) subpopulation at a frequency of 0.000466 (31/66568). This frequency is about 7 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this is likely a benign polymorphism found primarily in populations of European (Non-Finnish) origin. Multiple clinical diagnostic laboratories/reputable databases have conflicting classifications for this variant, most of which are benign or likely benign (benign [2x], likely benign [3x], and uncertain significance [2x]). To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Breast and/or ovarian cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 03, 2020

- -

Familial cancer of breast;C1836860:Fanconi anemia complementation group J

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Familial cancer of breast

Benign:1

Benign, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Mar 01, 2023

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Ovarian neoplasm

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Oct 26, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

7.2

DANN

Benign

0.57

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over