22-50744929-C-T

Position:

• chr22-50744929-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001097.3(ACR):​c.988C>T​(p.Pro330Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000349 in 1,430,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 14)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: ACR NM_001097.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.224

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.087782025).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACR	NM_001097.3	c.988C>T	p.Pro330Ser	missense_variant	5/5	ENST00000216139.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACR	ENST00000216139.10	c.988C>T	p.Pro330Ser	missense_variant	5/5	1	NM_001097.3	P1
ACR	ENST00000527761.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 14

GnomAD4 exome AF: 0.00000349 AC: 5 AN: 1430656 Hom.: 0 Cov.: 39 AF XY: 0.00000141 AC XY: 1 AN XY: 707606

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000457

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 14

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2024

The c.988C>T (p.P330S) alteration is located in exon 5 (coding exon 5) of the ACR gene. This alteration results from a C to T substitution at nucleotide position 988, causing the proline (P) at amino acid position 330 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	4.9
DANN	Benign	0.92
DEOGEN2	Benign	0.39	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.13	N
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.23
Sift	Benign	0.85	T
Sift4G	Benign	0.78	T
Polyphen		0.12	B
Vest4		0.14
MutPred		0.22		Loss of catalytic residue at P330 (P = 0.0047);
MVP		0.89
ClinPred		0.070	T
GERP RS		2.6
Varity_R		0.048
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1485964688; hg19: chr22-51183357;