rs777068696

Positions:

• chr17-61857130-C-A
• chr17-61857130-C-G
• chr17-61857130-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_032043.3(BRIP1):​c.307G>T​(p.Gly103Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRIP1 NM_032043.3 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.71

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-61857130-C-A is Pathogenic according to our data. Variant chr17-61857130-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 545988.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.307G>T	p.Gly103Ter	stop_gained	4/20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.307G>T	p.Gly103Ter	stop_gained	4/20	1	NM_032043.3	ENSP00000259008	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 14, 2016

This variant is denoted BRIP1 c.307G>T at the cDNA level and p.Gly103Ter (G103X) at the protein level. The substitution creates a nonsense variant, which changes a Glycine to a premature stop codon (GGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.66	D
MutationTaster	Benign	1.0	A;A
Vest4		0.76
GERP RS		3.2

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

Other links and lift over

dbSNP: rs777068696; hg19: chr17-59934491;