3-57074167-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_181727.2(SPATA12):​c.473C>T​(p.Thr158Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Consequence

SPATA12
NM_181727.2 missense

Scores

1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.43
Variant links:
Genes affected
SPATA12 (HGNC:23221): (spermatogenesis associated 12) This gene is expressed primarily in testis and may play a role in testicular development and spermatogenesis. The encoded protein may be upregulated in response to ultraviolet-C radiation. [provided by RefSeq, Dec 2015]
ARHGEF3 (HGNC:683): (Rho guanine nucleotide exchange factor 3) Rho-like GTPases are involved in a variety of cellular processes, and they are activated by binding GTP and inactivated by conversion of GTP to GDP by their intrinsic GTPase activity. Guanine nucleotide exchange factors (GEFs) accelerate the GTPase activity of Rho GTPases by catalyzing their release of bound GDP. This gene encodes a guanine nucleotide exchange factor, which specifically activates two members of the Rho GTPase family: RHOA and RHOB, both of which have a role in bone cell biology. It has been identified that genetic variation in this gene plays a role in the determination of bone mineral density (BMD), indicating the implication of this gene in postmenopausal osteoporosis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.060699493).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPATA12NM_181727.2 linkc.473C>T p.Thr158Ile missense_variant Exon 2 of 2 ENST00000334325.2 NP_859078.1 Q7Z6I5A0A140VJV7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPATA12ENST00000334325.2 linkc.473C>T p.Thr158Ile missense_variant Exon 2 of 2 1 NM_181727.2 ENSP00000335392.1 Q7Z6I5

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152160
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
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
GnomAD4 exome
Cov.:
31
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152160
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 23, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.473C>T (p.T158I) alteration is located in exon 2 (coding exon 1) of the SPATA12 gene. This alteration results from a C to T substitution at nucleotide position 473, causing the threonine (T) at amino acid position 158 to be replaced by an isoleucine (I). 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
0.23
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.69
CADD
Benign
16
DANN
Benign
0.88
DEOGEN2
Benign
0.21
T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.015
N
LIST_S2
Benign
0.43
T
M_CAP
Benign
0.00095
T
MetaRNN
Benign
0.061
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N
PrimateAI
Benign
0.31
T
PROVEAN
Pathogenic
-6.0
D
REVEL
Benign
0.14
Polyphen
0.036
B
Vest4
0.084
MutPred
0.14
Loss of relative solvent accessibility (P = 0.0404);
MVP
0.030
MPC
0.32
ClinPred
0.071
T
GERP RS
0.47
Varity_R
0.30
gMVP
0.034

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

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

Other links and lift over

dbSNP: rs1405547984; hg19: chr3-57108195; API