17-32996940-C-A

Variant names:

• chr17-32996940-C-A
• NM_173847.5:c.441C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_173847.5(SPACA3):​c.441C>A​(p.Ser147Arg) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPACA3 NM_173847.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.570

Genes affected

SPACA3 (HGNC:16260): (sperm acrosome associated 3) The protein encoded by this gene is a sperm surface protein that may be involved in adhesion to the egg prior to fertilization. While the encoded protein has significant similarity to lysozyme at the amino acid level, it has no detectable bacteriocidal activity. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPACA3	NM_173847.5	c.441C>A	p.Ser147Arg	missense_variant	Exon 3 of 5	ENST00000269053.8	NP_776246.1
SPACA3	NM_001317225.2	c.165C>A	p.Ser55Arg	missense_variant	Exon 3 of 5		NP_001304154.1
SPACA3	NM_001317226.2	c.132C>A	p.Ser44Arg	missense_variant	Exon 2 of 4		NP_001304155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPACA3	ENST00000269053.8	c.441C>A	p.Ser147Arg	missense_variant	Exon 3 of 5	1	NM_173847.5	ENSP00000269053.3
SPACA3	ENST00000580599.5	c.234C>A	p.Ser78Arg	missense_variant	Exon 4 of 6	1		ENSP00000463386.1
SPACA3	ENST00000394637.2	n.584C>A		non_coding_transcript_exon_variant	Exon 3 of 5	1
SPACA3	ENST00000394638.1	c.132C>A	p.Ser44Arg	missense_variant	Exon 2 of 4	3		ENSP00000378134.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.441C>A (p.S147R) alteration is located in exon 3 (coding exon 3) of the SPACA3 gene. This alteration results from a C to A substitution at nucleotide position 441, causing the serine (S) at amino acid position 147 to be replaced by an arginine (R). 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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	-0.067	T
MutationAssessor	Pathogenic	3.5	.;H;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.8	.;D;D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	.;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.87
MutPred		0.93		.;Gain of MoRF binding (P = 0.053);.;
MVP		0.85
MPC		0.46
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.93
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-31323958;