Genetic Variant SPATA3:p.His109Leu (chr2-231000390-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_139073.5(SPATA3):c.326A>T(p.His109Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,373,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

SPATA3
NM_139073.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.31

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07065663).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPATA3	NM_139073.5 link	c.326A>T	p.His109Leu	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.326A>T	p.His109Leu	missense_variant	Exon 2 of 5	1	NM_139073.5	ENSP00000403804.2		Q8NHX4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000694

AC:

AN:

144122

AF XY:

0.0000131

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000999

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000146

AC:

AN:

1373460

Hom.:

Cov.:

AF XY:

0.00000297

AC XY:

AN XY:

674274

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30906

American (AMR)

AF:

0.00

AC:

AN:

33130

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24266

East Asian (EAS)

AF:

0.0000288

AC:

AN:

34776

South Asian (SAS)

AF:

0.00

AC:

AN:

76848

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48700

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5608

European-Non Finnish (NFE)

AF:

9.41e-7

AC:

AN:

1062652

Other (OTH)

AF:

0.00

AC:

AN:

56574

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 26, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.326A>T (p.H109L) alteration is located in exon 2 (coding exon 2) of the SPATA3 gene. This alteration results from a A to T substitution at nucleotide position 326, causing the histidine (H) at amino acid position 109 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

0.10

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.16

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.0090

.;T;T;T;.;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.29

T;.;.;.;T;T

M_CAP

Benign

0.0021

MetaRNN

Benign

0.071

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

.;N;N;N;.;N

PhyloP100

-1.3

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.0

.;D;D;D;.;D

REVEL

Benign

0.018

Sift

Benign

0.050

.;D;D;D;.;D

Sift4G

Uncertain

0.027

.;D;D;D;D;D

Vest4

0.15, 0.21

MVP

0.14

ClinPred

0.032

GERP RS

-8.2

Varity_R

0.10

gMVP

0.012

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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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2-231000390-A-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over