2-230996244-T-C

Variant names:

• chr2-230996244-T-C
• rs955559993
• NM_139073.5:c.11T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_139073.5(SPATA3):​c.11T>C​(p.Val4Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000071 in 1,548,588 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: 𝑓 0.000033 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: SPATA3 NM_139073.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.748
• 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-AS1 (HGNC:28013): (SPATA3 antisense RNA 1 (head to head))

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03951767).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPATA3	NM_139073.5	c.11T>C	p.Val4Ala	missense_variant	Exon 1 of 5	ENST00000433428.7	NP_620712.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPATA3	ENST00000433428.7	c.11T>C	p.Val4Ala	missense_variant	Exon 1 of 5	1	NM_139073.5	ENSP00000403804.2

Frequencies

GnomAD3 genomes AF: 0.0000334 AC: 5 AN: 149726 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000123

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: 0.0000191 AC: 3 AN: 156902 AF XY: 0.0000242

Gnomad AFR exome AF: 0.000365

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: 0.00000429 AC: 6 AN: 1398862 Hom.: 0 Cov.: 32 AF XY: 0.00000725 AC XY: 5 AN XY: 689898

African (AFR) AF: 0.000190 AC: 6 AN: 31572

American (AMR) AF: 0.00 AC: 0 AN: 35552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25100

East Asian (EAS) AF: 0.00 AC: 0 AN: 35728

South Asian (SAS) AF: 0.00 AC: 0 AN: 79174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078694

Other (OTH) AF: 0.00 AC: 0 AN: 58122

GnomAD4 genome AF: 0.0000334 AC: 5 AN: 149726 Hom.: 0 Cov.: 29 AF XY: 0.0000274 AC XY: 2 AN XY: 72994

African (AFR) AF: 0.000123 AC: 5 AN: 40502

American (AMR) AF: 0.00 AC: 0 AN: 15056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.00 AC: 0 AN: 5050

South Asian (SAS) AF: 0.00 AC: 0 AN: 4714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67348

Other (OTH) AF: 0.00 AC: 0 AN: 2056

Alfa AF: 0.000106 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.11T>C (p.V4A) alteration is located in exon 1 (coding exon 1) of the SPATA3 gene. This alteration results from a T to C substitution at nucleotide position 11, causing the valine (V) at amino acid position 4 to be replaced by an alanine (A). 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	Uncertain	0.36
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	11
DANN	Benign	0.69
DEOGEN2	Benign	0.0032	T;T;T;.;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.38	.;.;.;T;T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.040	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;N;.;N
PhyloP100		0.75
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.53	N;N;N;.;N
REVEL	Benign	0.037
Sift	Benign	1.0	T;T;T;.;T
Sift4G	Benign	1.0	T;T;T;T;T
Vest4		0.11
MVP		0.12
ClinPred		0.033	T
GERP RS		0.48
PromoterAI		0.035	Neutral
Varity_R		0.036
gMVP		0.083
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs955559993; hg19: chr2-231860959;