rs3092989

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001136571.2(ZAR1L):c.-390+89C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 152,490 control chromosomes in the GnomAD database, including 2,432 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.17 ( 2424 hom., cov: 32)

Exomes 𝑓: 0.17 ( 8 hom. )

Consequence

ZAR1L
NM_001136571.2 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:2

Conservation

PhyloP100: -0.101

Publications

15 publications found

Variant links:

Genes affected

ZAR1L (HGNC:37116): (zygote arrest 1 like) This gene encodes a member of the ZAR1 family that is predominantly expressed in oocytes and early embryos. The protein may function as an RNA regulator in early embryos. [provided by RefSeq, Apr 2010]

ZAR1L links:

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

BRCA2 Gene-Disease associations (from GenCC):

breast-ovarian cancer, familial, susceptibility to, 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
Fanconi anemia complementation group D1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
pancreatic cancer, susceptibility to, 2
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary breast ovarian cancer syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
medulloblastoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 13-32315226-G-A is Benign according to our data. Variant chr13-32315226-G-A is described in ClinVar as [Benign]. Clinvar id is 209598.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZAR1L	NM_001136571.2 link	c.-390+89C>T		intron_variant	Intron 1 of 5	ENST00000533490.7	NP_001130043.1	A6NP61
BRCA2	NM_001432077.1 link	c.-40+81G>A		intron_variant	Intron 1 of 26		NP_001419006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZAR1L	ENST00000533490.7 link	c.-390+89C>T		intron_variant	Intron 1 of 5	5	NM_001136571.2	ENSP00000437289.2		A6NP61
BRCA2	ENST00000544455.6 link	c.-40+81G>A		intron_variant	Intron 1 of 26	1		ENSP00000439902.1		P51587

Frequencies

GnomAD3 genomes

AF:

0.173

AC:

26288

AN:

151952

Hom.:

2420

Cov.:

show subpopulations

Gnomad AFR

AF:

0.149

Gnomad AMI

AF:

0.178

Gnomad AMR

AF:

0.201

Gnomad ASJ

AF:

0.153

Gnomad EAS

AF:

0.149

Gnomad SAS

AF:

0.122

Gnomad FIN

AF:

0.236

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.178

Gnomad OTH

AF:

0.176

GnomAD4 exome

AF:

0.167

AC:

AN:

420

Hom.:

AF XY:

0.171

AC XY:

AN XY:

310

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.250

AC:

AN:

European-Finnish (FIN)

AF:

0.250

AC:

AN:

Middle Eastern (MID)

AF:

0.167

AC:

AN:

European-Non Finnish (NFE)

AF:

0.154

AC:

AN:

356

Other (OTH)

AF:

0.444

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.173

AC:

26319

AN:

152070

Hom.:

2424

Cov.:

AF XY:

0.175

AC XY:

13008

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.150

AC:

6201

AN:

41474

American (AMR)

AF:

0.202

AC:

3080

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.153

AC:

531

AN:

3472

East Asian (EAS)

AF:

0.150

AC:

772

AN:

5160

South Asian (SAS)

AF:

0.122

AC:

587

AN:

4816

European-Finnish (FIN)

AF:

0.236

AC:

2493

AN:

10580

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.178

AC:

12089

AN:

67976

Other (OTH)

AF:

0.175

AC:

369

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1101

2203

3304

4406

5507

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.172

Hom.:

3964

Bravo

AF:

0.172

Asia WGS

AF:

0.161

AC:

559

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Benign:1

Jan 12, 2015

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.16 (Asian), 0.18 (African), 0.18 (European), derived from 1000 genomes (2012-04-30). -

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

-0.79

CADD

Benign

1.8

(source)

DANN

Benign

0.90

PhyloP100

-0.10

PromoterAI

-0.0034

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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rs3092989

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over