22-50744084-A-C

Variant names:

• chr22-50744084-A-C
• rs2083438449
• NM_001097.3:c.589A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001097.3(ACR):​c.589A>C​(p.Met197Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: ACR NM_001097.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34523642).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACR	NM_001097.3	c.589A>C	p.Met197Leu	missense_variant	Exon 4 of 5	ENST00000216139.10	NP_001088.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACR	ENST00000216139.10	c.589A>C	p.Met197Leu	missense_variant	Exon 4 of 5	1	NM_001097.3	ENSP00000216139.5
ACR	ENST00000527761.1	n.-60A>C		upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 29

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.589A>C (p.M197L) alteration is located in exon 4 (coding exon 4) of the ACR gene. This alteration results from a A to C substitution at nucleotide position 589, causing the methionine (M) at amino acid position 197 to be replaced by a leucine (L). 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	0.15
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.58
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.023	N
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.10
Sift	Benign	0.12	T
Sift4G	Benign	0.083	T
Polyphen		0.0010	B
Vest4		0.19
MutPred		0.72		Gain of sheet (P = 0.1451);
MVP		0.56
ClinPred		0.18	T
GERP RS		-0.51
Varity_R		0.13
gMVP		0.53

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: rs2083438449; hg19: chr22-51182512;