Genetic Variant SPATA3:p.Gly127Trp (chr2-231000443-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_139073.5(SPATA3):c.379G>T(p.Gly127Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000419 in 1,549,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G127E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

SPATA3
NM_139073.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.84

Publications

0 publications found

Variant links:

Genes affected

SPATA3 (HGNC:17884): (spermatogenesis associated 3) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SPATA3 Gene-Disease associations (from GenCC):

male infertility with azoospermia or oligozoospermia due to single gene mutation
Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center

SPATA3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07048458).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPATA3	NM_139073.5 link	c.379G>T	p.Gly127Trp	missense_variant	Exon 2 of 5	ENST00000433428.7	NP_620712.2	Q8NHX4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPATA3	ENST00000433428.7 link	c.379G>T	p.Gly127Trp	missense_variant	Exon 2 of 5	1	NM_139073.5	ENSP00000403804.2		Q8NHX4

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000643

AC:

AN:

155484

AF XY:

0.0000485

show subpopulations

Gnomad AFR exome

AF:

0.00127

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000200

AC:

AN:

1397222

Hom.:

Cov.:

AF XY:

0.0000160

AC XY:

AN XY:

688942

show subpopulations

African (AFR)

AF:

0.000761

AC:

AN:

31540

American (AMR)

AF:

0.00

AC:

AN:

35518

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25138

East Asian (EAS)

AF:

0.00

AC:

AN:

35608

South Asian (SAS)

AF:

0.00

AC:

AN:

79090

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49238

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

9.28e-7

AC:

AN:

1077478

Other (OTH)

AF:

0.0000518

AC:

AN:

57920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000243

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.000890

AC:

AN:

41552

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000333

Hom.:

Bravo

AF:

0.000238

ESP6500AA

AF:

0.00217

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000187

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 29, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.379G>T (p.G127W) alteration is located in exon 2 (coding exon 2) of the SPATA3 gene. This alteration results from a G to T substitution at nucleotide position 379, causing the glycine (G) at amino acid position 127 to be replaced by a tryptophan (W). 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

0.93

BayesDel_addAF

Uncertain

0.090

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.055

.;T;T;T;.;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.81

T;.;.;.;T;T

M_CAP

Benign

0.0076

MetaRNN

Benign

0.070

T;T;T;T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.0

.;L;L;L;.;L

PhyloP100

3.8

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.8

.;D;D;D;.;D

REVEL

Uncertain

0.36

Sift

Pathogenic

0.0

.;D;D;D;.;D

Sift4G

Pathogenic

0.0

.;D;D;D;D;D

Vest4

0.87, 0.87

MVP

0.31

ClinPred

0.54

GERP RS

4.3

Varity_R

0.68

gMVP

0.091

Mutation Taster

=85/15

polymorphism

(source)

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

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2-231000443-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over