rs3092989

Positions:

• chr13-32315226-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: -0.101

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]

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]

ACMG classification

Verdict is Benign. Variant got -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. Variant chr13-32315226-G-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
ZAR1L	NM_001136571.2	c.-390+89C>T		intron_variant		ENST00000533490.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZAR1L	ENST00000533490.7	c.-390+89C>T		intron_variant		5	NM_001136571.2	P1
BRCA2	ENST00000544455.6	c.-40+81G>A		intron_variant		1		A2

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26288 AN: 151952 Hom.: 2420 Cov.: 32

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: 70 AN: 420 Hom.: 8 AF XY: 0.171 AC XY: 53 AN XY: 310

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.250

Gnomad4 FIN exome AF: 0.250

Gnomad4 NFE exome AF: 0.154

Gnomad4 OTH exome AF: 0.444

GnomAD4 genome AF: 0.173 AC: 26319 AN: 152070 Hom.: 2424 Cov.: 32 AF XY: 0.175 AC XY: 13008 AN XY: 74326

Gnomad4 AFR AF: 0.150

Gnomad4 AMR AF: 0.202

Gnomad4 ASJ AF: 0.153

Gnomad4 EAS AF: 0.150

Gnomad4 SAS AF: 0.122

Gnomad4 FIN AF: 0.236

Gnomad4 NFE AF: 0.178

Gnomad4 OTH AF: 0.175

Alfa AF: 0.172 Hom.: 1133

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

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:1

Benign, reviewed by expert panel

curation

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

Jan 12, 2015

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.8
DANN	Benign	0.90

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

LitVar

Other links and lift over

dbSNP: rs3092989; hg19: chr13-32889363;