Variant 17-32996849-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_173847.5(SPACA3):c.350G>T(p.Cys117Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,441,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SPACA3
NM_173847.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.89

Variant links:

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]

SPACA3 links:

SPACA3 (HGNC:):

SPACA3 links:

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ACMG classification

Classification made for transcript

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, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPACA3	NM_173847.5 linkuse as main transcript	c.350G>T	p.Cys117Phe	missense_variant	3/5	ENST00000269053.8	NP_776246.1	Q8IXA5-1A0A080YUZ7
SPACA3	NM_001317225.2 linkuse as main transcript	c.74G>T	p.Cys25Phe	missense_variant	3/5		NP_001304154.1	Q05C28
SPACA3	NM_001317226.2 linkuse as main transcript	c.41G>T	p.Cys14Phe	missense_variant	2/4		NP_001304155.1	Q8IXA5E9PF91

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SPACA3	ENST00000269053.8 linkuse as main transcript	c.350G>T	p.Cys117Phe	missense_variant	3/5	1	NM_173847.5	ENSP00000269053.3	Q8IXA5-1
SPACA3	ENST00000580599.5 linkuse as main transcript	c.143G>T	p.Cys48Phe	missense_variant	4/6	1		ENSP00000463386.1	Q8IXA5-2
SPACA3	ENST00000394637.2 linkuse as main transcript	n.493G>T		non_coding_transcript_exon_variant	3/5	1
SPACA3	ENST00000394638.1 linkuse as main transcript	c.41G>T	p.Cys14Phe	missense_variant	2/4	3		ENSP00000378134.1	E9PF91

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000427

AC:

AN:

234066

Hom.:

AF XY:

0.00000795

AC XY:

AN XY:

125756

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000564

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000208

AC:

AN:

1441826

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

715756

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000766

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2024

The c.350G>T (p.C117F) alteration is located in exon 3 (coding exon 3) of the SPACA3 gene. This alteration results from a G to T substitution at nucleotide position 350, causing the cysteine (C) at amino acid position 117 to be replaced by a phenylalanine (F). 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

0.91

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

.;T;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.88

D;D;T

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

0.51

MutationAssessor

Pathogenic

4.1

.;H;.

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-11

.;D;D

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.80

MutPred

0.93

.;Loss of catalytic residue at L118 (P = 0.0226);.;

MVP

0.94

MPC

0.53

ClinPred

1.0

GERP RS

3.6

Varity_R

0.97

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over