3-57073783-T-A

Variant names:

• chr3-57073783-T-A
• rs748009888
• NM_181727.2:c.89T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181727.2(SPATA12):​c.89T>A​(p.Val30Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SPATA12 NM_181727.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.509
• Publications: 0 publications found

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]

ACMG classification

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=0.22117758).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181727.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPATA12	NM_181727.2	MANE Select	c.89T>A	p.Val30Asp	missense	Exon 2 of 2	NP_859078.1	A0A140VJV7
	ARHGEF3	NM_001128615.2		c.-28+5443A>T		intron	N/A	NP_001122087.1	Q9NR81-2
	ARHGEF3	NM_001377407.1		c.-28+4764A>T		intron	N/A	NP_001364336.1	Q9NR81-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPATA12	ENST00000334325.2	TSL:1 MANE Select	c.89T>A	p.Val30Asp	missense	Exon 2 of 2	ENSP00000335392.1	Q7Z6I5
	ARHGEF3	ENST00000338458.8	TSL:1	c.-28+5443A>T		intron	N/A	ENSP00000341071.4	Q9NR81-2
	SPATA12	ENST00000867038.1		c.89T>A	p.Val30Asp	missense	Exon 2 of 2	ENSP00000537097.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000278 AC: 7 AN: 251450 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.71
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.51
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Benign	0.16
Polyphen		0.91	P
Vest4		0.52
MutPred		0.15		Loss of glycosylation at P34 (P = 0.035)
MVP		0.072
MPC		0.17
ClinPred		0.23	T
GERP RS		-0.59
Varity_R		0.42
gMVP		0.13
Mutation Taster		=100/0	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: rs748009888; hg19: chr3-57107811;