rs28368062

chr20-57329973-A-Cchr20-57329973-A-Gchr20-57329973-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012444.3(SPO11):c.106A>C(p.Thr36Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000535 in 1,608,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T36A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: SPO11 NM_012444.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0300

Genes affected

SPO11 (HGNC:11250): (SPO11 initiator of meiotic double strand breaks) Meiotic recombination and chromosome segregation require the formation of double-strand breaks (DSBs) in paired chromosome homologs. During meiosis in yeast, a meiotic recombination protein is covalently-linked to the 5' end of DSBs and is essential for the formation of DSBs. The protein encoded by this gene is similar in sequence and conserved features to the yeast meiotic recombination protein. The encoded protein belongs to the TOP6A protein family. Several transcript variants encoding different isoforms have been found for this gene, but the full-length nature of only two of them have been described. [provided by RefSeq, Jul 2008]

ACMG classification

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=0.016748458).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPO11	NM_012444.3	c.106A>C	p.Thr36Pro	missense_variant	1/13	ENST00000371263.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPO11	ENST00000371263.8	c.106A>C	p.Thr36Pro	missense_variant	1/13	1	NM_012444.3	P1
SPO11	ENST00000345868.8	c.106A>C	p.Thr36Pro	missense_variant	1/12	1
SPO11	ENST00000371260.8	c.106A>C	p.Thr36Pro	missense_variant	1/12	5
SPO11	ENST00000418127.5	c.40A>C	p.Thr14Pro	missense_variant	1/10	3

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000844

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: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000465 AC: 11 AN: 236762 Hom.: 0 AF XY: 0.0000309 AC XY: 4 AN XY: 129410

Gnomad AFR exome AF: 0.000756

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.0000309 AC: 45 AN: 1456150 Hom.: 0 Cov.: 30 AF XY: 0.0000331 AC XY: 24 AN XY: 724224

Gnomad4 AFR exome AF: 0.000599

Gnomad4 AMR exome AF: 0.0000227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.0000831

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74486

Gnomad4 AFR AF: 0.000938

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: 0.000474

ExAC AF: 0.0000577 AC: 7

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	2.6
Dann	Benign	0.45
DEOGEN2	Benign	0.086	T;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.071	T;T;T;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.017	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.37	N;N;N;N
REVEL	Benign	0.080
Sift	Benign	0.29	T;T;T;T
Sift4G	Benign	0.31	T;T;T;T
Polyphen		0.0	B;B;.;.
Vest4		0.099
MVP		0.47
MPC		0.070
ClinPred		0.017	T
GERP RS		0.22
Varity_R		0.074
gMVP		0.31

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

Other links and lift over

dbSNP: rs28368062; hg19: chr20-55905029;