chr17-61685976-A-G

Position:

• chr17-61685976-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1 PM2 BP4_Moderate BP6

The NM_032043.3(BRIP1):​c.2765T>C​(p.Leu922Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Synonymous variant affecting the same amino acid position (i.e. L922L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.834

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 Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain in NM_032043.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16136938).
• BP6: Variant 17-61685976-A-G is Benign according to our data. Variant chr17-61685976-A-G is described in ClinVar as [Benign]. Clinvar id is 873415.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3	c.2765T>C	p.Leu922Ser	missense_variant	19/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7	c.2765T>C	p.Leu922Ser	missense_variant	19/20	1	NM_032043.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

research

King Laboratory, University of Washington

Sep 01, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	13
DANN	Uncertain	1.0
DEOGEN2	Benign	0.080	T;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.32	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.53	N;.
REVEL	Benign	0.18
Sift	Benign	0.051	T;.
Sift4G	Benign	0.52	T;T
Polyphen		0.50	P;.
Vest4		0.16
MutPred		0.48		Gain of disorder (P = 0.0061);Gain of disorder (P = 0.0061);
MVP		0.81
MPC		0.31
ClinPred		0.28	T
GERP RS		4.7
Varity_R		0.071
gMVP		0.33

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: rs587782410; hg19: chr17-59763337;