chr2-231000443-G-T

Variant names:

• chr2-231000443-G-T
• rs370099747
• NM_139073.5:c.379G>T

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.84
• Publications: 0 publications found

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

ACMG classification

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	c.379G>T	p.Gly127Trp	missense_variant	Exon 2 of 5	ENST00000433428.7	NP_620712.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152128 Hom.: 0 Cov.: 33

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: 10 AN: 155484 AF XY: 0.0000485

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: 28 AN: 1397222 Hom.: 0 Cov.: 38 AF XY: 0.0000160 AC XY: 11 AN XY: 688942

African (AFR) AF: 0.000761 AC: 24 AN: 31540

American (AMR) AF: 0.00 AC: 0 AN: 35518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25138

East Asian (EAS) AF: 0.00 AC: 0 AN: 35608

South Asian (SAS) AF: 0.00 AC: 0 AN: 79090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1077478

Other (OTH) AF: 0.0000518 AC: 3 AN: 57920

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74430

African (AFR) AF: 0.000890 AC: 37 AN: 41552

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.0000333 Hom.: 0

Bravo AF: 0.000238

ESP6500AA AF: 0.00217 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000187 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
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	D
LIST_S2	Benign	0.81	T;.;.;.;T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.070	T;T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.0	.;L;L;L;.;L
PhyloP100		3.8
PrimateAI	Uncertain	0.62	T
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	D
GERP RS		4.3
Varity_R		0.68
gMVP		0.091
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs370099747; hg19: chr2-231865158;