chr22-50744057-A-G

Variant names:

• chr22-50744057-A-G
• rs6009961
• NM_001097.3:c.566-4A>G

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.0001893
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.377
• Publications: 10 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001097.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACR	NM_001097.3	MANE Select	c.566-4A>G		splice_region intron	N/A	NP_001088.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACR	ENST00000216139.10	TSL:1 MANE Select	c.566-4A>G		splice_region intron	N/A	ENSP00000216139.5
	ACR	ENST00000527761.1	TSL:5	n.-87A>G		upstream_gene	N/A

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

GnomAD2 exomes AF: 0.657 AC: 161125 AN: 245076 AF XY: 0.653

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.893 AC: 28136 AN: 31510

American (AMR) AF: 0.579 AC: 25279 AN: 43666

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 17668 AN: 25168

East Asian (EAS) AF: 0.396 AC: 15451 AN: 39020

South Asian (SAS) AF: 0.541 AC: 44979 AN: 83090

European-Finnish (FIN) AF: 0.711 AC: 37168 AN: 52246

Middle Eastern (MID) AF: 0.556 AC: 3032 AN: 5450

European-Non Finnish (NFE) AF: 0.731 AC: 726799 AN: 994930

Other (OTH) AF: 0.705 AC: 39523 AN: 56048

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.877 AC: 36037 AN: 41080

American (AMR) AF: 0.662 AC: 10027 AN: 15140

Ashkenazi Jewish (ASJ) AF: 0.717 AC: 2477 AN: 3456

East Asian (EAS) AF: 0.420 AC: 2150 AN: 5118

South Asian (SAS) AF: 0.531 AC: 2545 AN: 4794

European-Finnish (FIN) AF: 0.702 AC: 7322 AN: 10432

Middle Eastern (MID) AF: 0.575 AC: 168 AN: 292

European-Non Finnish (NFE) AF: 0.715 AC: 48420 AN: 67674

Other (OTH) AF: 0.739 AC: 1544 AN: 2090

Alfa AF: 0.715 Hom.: 15975

Bravo AF: 0.739

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	5.1
DANN	Benign	0.75
PhyloP100		-0.38
Mutation Taster		=59/41	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6009961; hg19: chr22-51182485; COSMIC: COSV53360590; COSMIC: COSV53360590;