20-57329974-C-T

Variant summary

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

The NM_012444.3(SPO11):c.107C>T(p.Thr36Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,607,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. T36A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

SPO11
NM_012444.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.62

Variant links:

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]

SPO11 links:

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=0.045173317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPO11	NM_012444.3 linkuse as main transcript	c.107C>T	p.Thr36Ile	missense_variant	1/13	ENST00000371263.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPO11	ENST00000371263.8 linkuse as main transcript	c.107C>T	p.Thr36Ile	missense_variant	1/13	1	NM_012444.3	P1	Q9Y5K1-1
SPO11	ENST00000345868.8 linkuse as main transcript	c.107C>T	p.Thr36Ile	missense_variant	1/12	1			Q9Y5K1-2
SPO11	ENST00000371260.8 linkuse as main transcript	c.107C>T	p.Thr36Ile	missense_variant	1/12	5
SPO11	ENST00000418127.5 linkuse as main transcript	c.41C>T	p.Thr14Ile	missense_variant	1/10	3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000170

AC:

AN:

235380

Hom.:

AF XY:

0.0000155

AC XY:

AN XY:

128754

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000309

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000949

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000962

AC:

AN:

1455462

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

723908

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000269

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000453

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2023

The c.107C>T (p.T36I) alteration is located in exon 1 (coding exon 1) of the SPO11 gene. This alteration results from a C to T substitution at nucleotide position 107, causing the threonine (T) at amino acid position 36 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

0.080

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

Cadd

Benign

0.13

Dann

Benign

0.96

DEOGEN2

Benign

0.059

T;.;.;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.24

T;T;T;T

M_CAP

Benign

0.0063

MetaRNN

Benign

0.045

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

0.34

N;N;N;N

REVEL

Benign

0.0070

Sift

Benign

0.15

T;T;T;T

Sift4G

Benign

0.19

T;T;T;T

Polyphen

0.0020

B;B;.;.

Vest4

0.13

MVP

0.35

MPC

0.062

ClinPred

0.086

GERP RS

-3.5

Varity_R

0.028

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over