chr17-61847144-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_032043.3(BRIP1):c.584T>C(p.Leu195Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,613,712 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L195R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 6 hom. )

Consequence

BRIP1
NM_032043.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26O:1

Conservation

PhyloP100: 0.364

Publications

19 publications found

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 Gene-Disease associations (from GenCC):

familial ovarian cancer
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Fanconi anemia
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
Fanconi anemia complementation group J
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: STRONG, LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, ClinGen
colorectal adenoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

BRIP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004298687).

BP6

Variant 17-61847144-A-G is Benign according to our data. Variant chr17-61847144-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 6 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032043.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRIP1	NM_032043.3	MANE Select	c.584T>C	p.Leu195Pro	missense	Exon 6 of 20	NP_114432.2	Q9BX63-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BRIP1	ENST00000259008.7	TSL:1 MANE Select	c.584T>C	p.Leu195Pro	missense	Exon 6 of 20	ENSP00000259008.2	Q9BX63-1
BRIP1	ENST00000682453.1		c.584T>C	p.Leu195Pro	missense	Exon 7 of 21	ENSP00000506943.1	Q9BX63-1
BRIP1	ENST00000683039.1		c.584T>C	p.Leu195Pro	missense	Exon 7 of 21	ENSP00000508303.1	Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.00189

AC:

287

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00923

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00207

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00194

AC:

487

AN:

251340

AF XY:

0.00200

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00911

Gnomad NFE exome

AF:

0.00202

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00228

AC:

3328

AN:

1461406

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

1589

AN XY:

727042

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33458

American (AMR)

AF:

0.000805

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.000417

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00800

AC:

427

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00242

AC:

2695

AN:

1111668

Other (OTH)

AF:

0.00204

AC:

123

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

169

338

507

676

845

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

220

330

440

550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00188

AC:

287

AN:

152306

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

151

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000505

AC:

AN:

41562

American (AMR)

AF:

0.00131

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00923

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00207

AC:

141

AN:

68016

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00154

Hom.:

Bravo

AF:

0.00120

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00160

AC:

194

Asia WGS

AF:

0.000289

AC:

AN:

3474

EpiCase

AF:

0.00202

EpiControl

AF:

0.00243

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

Hereditary cancer-predisposing syndrome (5)

not specified (5)

Familial cancer of breast (3)

Fanconi anemia complementation group J (3)

Breast and/or ovarian cancer (1)

BRIP1-related disorder (1)

Familial cancer of breast;C1836860:Fanconi anemia complementation group J (1)

Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.51

CADD

Benign

5.2

(source)

DANN

Benign

0.23

DEOGEN2

Benign

0.067

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.46

M_CAP

Benign

0.033

MetaRNN

Benign

0.0043

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.75

PhyloP100

0.36

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.10

REVEL

Benign

0.10

Sift

Benign

0.32

Sift4G

Benign

0.39

Polyphen

0.0

Vest4

0.13

MVP

0.41

MPC

0.26

ClinPred

0.0012

GERP RS

-0.011

PromoterAI

0.017

Neutral

(source)

Varity_R

0.032

gMVP

0.47

Mutation Taster

=85/15

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over