17-32997505-C-T

Position:

• chr17-32997505-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_173847.5(SPACA3):​c.563C>T​(p.Pro188Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000719 in 1,614,010 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P188A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0036 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00042 (3 hom.)
• Consequence: SPACA3 NM_173847.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.79

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008892834).
• BP6: Variant 17-32997505-C-T is Benign according to our data. Variant chr17-32997505-C-T is described in ClinVar as [Benign]. Clinvar id is 725292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPACA3	NM_173847.5	c.563C>T	p.Pro188Leu	missense_variant	4/5	ENST00000269053.8
SPACA3	NM_001317225.2	c.287C>T	p.Pro96Leu	missense_variant	4/5
SPACA3	NM_001317226.2	c.254C>T	p.Pro85Leu	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPACA3	ENST00000269053.8	c.563C>T	p.Pro188Leu	missense_variant	4/5	1	NM_173847.5	A2
SPACA3	ENST00000580599.5	c.356C>T	p.Pro119Leu	missense_variant	5/6	1		P2
SPACA3	ENST00000394637.2	n.706C>T		non_coding_transcript_exon_variant	4/5	1
SPACA3	ENST00000394638.1	c.254C>T	p.Pro85Leu	missense_variant	3/4	3

Frequencies

GnomAD3 genomes AF: 0.00356 AC: 542 AN: 152128 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00113 AC: 283 AN: 251448 Hom.: 3 AF XY: 0.000861 AC XY: 117 AN XY: 135906

Gnomad AFR exome AF: 0.0135

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000423 AC: 618 AN: 1461764 Hom.: 3 Cov.: 32 AF XY: 0.000364 AC XY: 265 AN XY: 727204

Gnomad4 AFR exome AF: 0.0127

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000342

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.00357 AC: 543 AN: 152246 Hom.: 1 Cov.: 31 AF XY: 0.00329 AC XY: 245 AN XY: 74444

Gnomad4 AFR AF: 0.0123

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000822 Hom.: 1

Bravo AF: 0.00401

ESP6500AA AF: 0.0136 AC: 60

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00132 AC: 160

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.040	.;T;.
Eigen	Benign	-0.0097
Eigen_PC	Benign	-0.084
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.85	T;T;D
MetaRNN	Benign	0.0089	T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	3.6	.;H;.
MutationTaster	Benign	0.91	D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.2	.;D;D
REVEL	Uncertain	0.35
Sift	Benign	0.033	.;D;D
Sift4G	Uncertain	0.041	D;T;D
Polyphen		0.72	.;P;.
Vest4		0.62
MVP		0.84
MPC		0.44
ClinPred		0.12	T
GERP RS		4.4
Varity_R		0.23
gMVP		0.56

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: rs35014584; hg19: chr17-31324523;