rs4988340

Variant names:

• chr17-61863272-C-T
• rs4988340
• NM_032043.3:c.-31+12G>A

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.-31+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 151,976 control chromosomes in the GnomAD database, including 5,520 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5518 hom., cov: 30)
  • Exomes 𝑓: 0.27 (2 hom.)
• Consequence: BRIP1 NM_032043.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0890
• Publications: 16 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=-0.69).
• BP6: Variant 17-61863272-C-T is Benign according to our data. Variant chr17-61863272-C-T is described in ClinVar as [Benign]. Clinvar id is 136585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.-31+12G>A		intron_variant	Intron 1 of 19	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.-31+12G>A		intron_variant	Intron 1 of 19	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38128 AN: 151796 Hom.: 5506 Cov.: 30

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.427

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.506

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.269

GnomAD4 exome AF: 0.274 AC: 17 AN: 62 Hom.: 2 Cov.: 0 AF XY: 0.261 AC XY: 12 AN XY: 46

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.375 AC: 3 AN: 8

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.280 AC: 14 AN: 50

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.251 AC: 38157 AN: 151914 Hom.: 5518 Cov.: 30 AF XY: 0.258 AC XY: 19133 AN XY: 74236

African (AFR) AF: 0.119 AC: 4947 AN: 41460

American (AMR) AF: 0.358 AC: 5462 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 975 AN: 3466

East Asian (EAS) AF: 0.274 AC: 1415 AN: 5158

South Asian (SAS) AF: 0.508 AC: 2428 AN: 4782

European-Finnish (FIN) AF: 0.256 AC: 2706 AN: 10558

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.282 AC: 19181 AN: 67922

Other (OTH) AF: 0.269 AC: 566 AN: 2108

Alfa AF: 0.275 Hom.: 23842

Bravo AF: 0.248

Asia WGS AF: 0.365 AC: 1271 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Sep 19, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	12
DANN	Benign	0.83
PhyloP100		0.089
PromoterAI		-0.085	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs4988340; hg19: chr17-59940633;