rs3092989

Variant names:

• chr13-32315226-G-A
• rs3092989
• NM_001136571.2:c.-390+89C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 15 publications found

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]

BRCA2 Gene-Disease associations (from GenCC):

• BRCA2-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136571.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZAR1L	NM_001136571.2	MANE Select	c.-390+89C>T		intron	N/A	NP_001130043.1	A6NP61
	BRCA2	NM_001432077.1		c.-40+81G>A		intron	N/A	NP_001419006.1	A0A7P0T9D7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZAR1L	ENST00000533490.7	TSL:5 MANE Select	c.-390+89C>T		intron	N/A	ENSP00000437289.2	A6NP61
	BRCA2	ENST00000544455.6	TSL:1	c.-40+81G>A		intron	N/A	ENSP00000439902.1	P51587

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

African (AFR) AF: 0.500 AC: 2 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.00 AC: 0 AN: 14

South Asian (SAS) AF: 0.250 AC: 2 AN: 8

European-Finnish (FIN) AF: 0.250 AC: 2 AN: 8

Middle Eastern (MID) AF: 0.167 AC: 1 AN: 6

European-Non Finnish (NFE) AF: 0.154 AC: 55 AN: 356

Other (OTH) AF: 0.444 AC: 8 AN: 18

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

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: 35 AN: 294

European-Non Finnish (NFE) AF: 0.178 AC: 12089 AN: 67976

Other (OTH) AF: 0.175 AC: 369 AN: 2106

Alfa AF: 0.172 Hom.: 3964

Bravo AF: 0.172

Asia WGS AF: 0.161 AC: 559 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Breast-ovarian cancer, familial, susceptibility to, 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.8
DANN	Benign	0.90
PhyloP100		-0.10
PromoterAI		-0.0034	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3092989; hg19: chr13-32889363;