17-61683138-A-G

Variant names:

• chr17-61683138-A-G
• rs1978111
• NM_032043.3:c.*158T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032043.3(BRIP1):​c.*158T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.595 in 929,366 control chromosomes in the GnomAD database, including 170,514 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (28545 hom., cov: 31)
  • Exomes 𝑓: 0.59 (141969 hom.)
• Consequence: BRIP1 NM_032043.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.426
• Publications: 8 publications found

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: Orphanet, Illumina
• Fanconi anemia complementation group J

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary breast carcinoma

  Inheritance: AD Classification: STRONG, LIMITED, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• colorectal adenoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-61683138-A-G is Benign according to our data. Variant chr17-61683138-A-G is described in ClinVar as Benign. ClinVar VariationId is 324344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.723 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.*158T>C		3_prime_UTR_variant	Exon 20 of 20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.*158T>C		3_prime_UTR_variant	Exon 20 of 20	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes AF: 0.606 AC: 92015 AN: 151786 Hom.: 28511 Cov.: 31

Gnomad AFR AF: 0.656

Gnomad AMI AF: 0.369

Gnomad AMR AF: 0.734

Gnomad ASJ AF: 0.586

Gnomad EAS AF: 0.720

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.655

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.630

GnomAD4 exome AF: 0.592 AC: 460403 AN: 777464 Hom.: 141969 Cov.: 10 AF XY: 0.587 AC XY: 232385 AN XY: 395888

African (AFR) AF: 0.662 AC: 12012 AN: 18154

American (AMR) AF: 0.767 AC: 14659 AN: 19100

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 8999 AN: 15752

East Asian (EAS) AF: 0.748 AC: 23832 AN: 31864

South Asian (SAS) AF: 0.459 AC: 23752 AN: 51706

European-Finnish (FIN) AF: 0.438 AC: 12804 AN: 29246

Middle Eastern (MID) AF: 0.647 AC: 1641 AN: 2536

European-Non Finnish (NFE) AF: 0.596 AC: 341238 AN: 572888

Other (OTH) AF: 0.593 AC: 21466 AN: 36218

GnomAD4 genome AF: 0.606 AC: 92110 AN: 151902 Hom.: 28545 Cov.: 31 AF XY: 0.601 AC XY: 44628 AN XY: 74262

African (AFR) AF: 0.656 AC: 27148 AN: 41406

American (AMR) AF: 0.734 AC: 11221 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.586 AC: 2034 AN: 3470

East Asian (EAS) AF: 0.721 AC: 3732 AN: 5176

South Asian (SAS) AF: 0.460 AC: 2205 AN: 4796

European-Finnish (FIN) AF: 0.408 AC: 4293 AN: 10518

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.583 AC: 39616 AN: 67940

Other (OTH) AF: 0.630 AC: 1331 AN: 2114

Alfa AF: 0.470 Hom.: 1420

Bravo AF: 0.636

Asia WGS AF: 0.534 AC: 1858 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Fanconi anemia complementation group J Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.49
DANN	Benign	0.56
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1978111; hg19: chr17-59760499;