22-50744057-A-G

Variant summary

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

The NM_001097.3(ACR):c.566-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 1,482,114 control chromosomes in the GnomAD database, including 387,615 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (41958 hom., cov: 26)
  • Exomes 𝑓: 0.70 (345657 hom.)
• Consequence: ACR NM_001097.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001893
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.377

Genes affected

ACR (HGNC:126): (acrosin) Acrosin is the major proteinase present in the acrosome of mature spermatozoa. It is a typical serine proteinase with trypsin-like specificity. It is stored in the acrosome in its precursor form, proacrosin. The active enzyme functions in the lysis of the zona pellucida, thus facilitating penetration of the sperm through the innermost glycoprotein layers of the ovum. The mRNA for proacrosin is synthesized only in the postmeiotic stages of spermatogenesis. In humans proacrosin first appears in the haploid spermatids. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 22-50744057-A-G is Benign according to our data. Variant chr22-50744057-A-G is described in ClinVar as [Benign]. Clinvar id is 402335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.87 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACR	NM_001097.3	c.566-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000216139.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACR	ENST00000216139.10	c.566-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001097.3	P1

Frequencies

GnomAD3 genomes AF: 0.737 AC: 111259 AN: 150872 Hom.: 41911 Cov.: 26

Gnomad AFR AF: 0.877

Gnomad AMI AF: 0.747

Gnomad AMR AF: 0.662

Gnomad ASJ AF: 0.717

Gnomad EAS AF: 0.419

Gnomad SAS AF: 0.531

Gnomad FIN AF: 0.702

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.716

Gnomad OTH AF: 0.736

GnomAD3 exomes AF: 0.657 AC: 161125 AN: 245076 Hom.: 54934 AF XY: 0.653 AC XY: 86473 AN XY: 132516

Gnomad AFR exome AF: 0.888

Gnomad AMR exome AF: 0.561

Gnomad ASJ exome AF: 0.702

Gnomad EAS exome AF: 0.411

Gnomad SAS exome AF: 0.538

Gnomad FIN exome AF: 0.699

Gnomad NFE exome AF: 0.713

Gnomad OTH exome AF: 0.667

GnomAD4 exome AF: 0.705 AC: 938035 AN: 1331128 Hom.: 345657 Cov.: 31 AF XY: 0.699 AC XY: 465895 AN XY: 666922

Gnomad4 AFR exome AF: 0.893

Gnomad4 AMR exome AF: 0.579

Gnomad4 ASJ exome AF: 0.702

Gnomad4 EAS exome AF: 0.396

Gnomad4 SAS exome AF: 0.541

Gnomad4 FIN exome AF: 0.711

Gnomad4 NFE exome AF: 0.731

Gnomad4 OTH exome AF: 0.705

GnomAD4 genome AF: 0.738 AC: 111370 AN: 150986 Hom.: 41958 Cov.: 26 AF XY: 0.728 AC XY: 53684 AN XY: 73694

Gnomad4 AFR AF: 0.877

Gnomad4 AMR AF: 0.662

Gnomad4 ASJ AF: 0.717

Gnomad4 EAS AF: 0.420

Gnomad4 SAS AF: 0.531

Gnomad4 FIN AF: 0.702

Gnomad4 NFE AF: 0.715

Gnomad4 OTH AF: 0.739

Alfa AF: 0.724 Hom.: 8417

Bravo AF: 0.739

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 66% of total chromosomes in ExAC -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	5.1
Dann	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.022
SpliceAI score (max)		0.080		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: rs6009961; hg19: chr22-51182485; COSMIC: COSV53360590; COSMIC: COSV53360590;