20-57329973-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_012444.3(SPO11):c.106A>G(p.Thr36Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,608,460 control chromosomes in the GnomAD database, including 181 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T36N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.020 ( 81 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 100 hom. )

Consequence

SPO11
NM_012444.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0300

Publications

4 publications found

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026219487).

BP6

Variant 20-57329973-A-G is Benign according to our data. Variant chr20-57329973-A-G is described in ClinVar as Benign. ClinVar VariationId is 785662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPO11	NM_012444.3 link	c.106A>G	p.Thr36Ala	missense_variant	Exon 1 of 13	ENST00000371263.8	NP_036576.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SPO11	ENST00000371263.8 link	c.106A>G	p.Thr36Ala	missense_variant	Exon 1 of 13	1	NM_012444.3	ENSP00000360310.3
SPO11	ENST00000345868.8 link	c.106A>G	p.Thr36Ala	missense_variant	Exon 1 of 12	1		ENSP00000316034.4
SPO11	ENST00000371260.8 link	c.106A>G	p.Thr36Ala	missense_variant	Exon 1 of 12	5		ENSP00000360307.4
SPO11	ENST00000418127.5 link	c.40A>G	p.Thr14Ala	missense_variant	Exon 1 of 10	3		ENSP00000413185.1

Frequencies

GnomAD3 genomes

AF:

0.0197

AC:

2995

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0680

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00857

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.00532

AC:

1259

AN:

236762

AF XY:

0.00381

show subpopulations

Gnomad AFR exome

AF:

0.0729

Gnomad AMR exome

AF:

0.00445

Gnomad ASJ exome

AF:

0.000103

Gnomad EAS exome

AF:

0.000227

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000292

Gnomad OTH exome

AF:

0.00172

GnomAD4 exome

AF:

0.00224

AC:

3258

AN:

1456146

Hom.:

100

Cov.:

AF XY:

0.00191

AC XY:

1383

AN XY:

724222

show subpopulations

African (AFR)

AF:

0.0758

AC:

2531

AN:

33410

American (AMR)

AF:

0.00478

AC:

211

AN:

44132

Ashkenazi Jewish (ASJ)

AF:

0.0000769

AC:

AN:

26004

East Asian (EAS)

AF:

0.0000758

AC:

AN:

39594

South Asian (SAS)

AF:

0.000291

AC:

AN:

85776

European-Finnish (FIN)

AF:

0.0000196

AC:

AN:

51142

Middle Eastern (MID)

AF:

0.00226

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.000168

AC:

187

AN:

1110160

Other (OTH)

AF:

0.00474

AC:

285

AN:

60176

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

150

301

451

602

752

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0197

AC:

2998

AN:

152314

Hom.:

Cov.:

AF XY:

0.0190

AC XY:

1414

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0679

AC:

2823

AN:

41582

American (AMR)

AF:

0.00856

AC:

131

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68014

Other (OTH)

AF:

0.0119

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

148

296

444

592

740

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00537

Hom.:

Bravo

AF:

0.0235

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0645

AC:

284

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00624

AC:

757

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 10, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.49

(source)

DANN

Benign

0.34

DEOGEN2

Benign

0.057

T;.;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0062

LIST_S2

Benign

0.074

T;T;T;T

MetaRNN

Benign

0.0026

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.69

N;N;.;.

PhyloP100

-0.030

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.18

N;N;N;N

REVEL

Benign

0.036

Sift

Benign

0.77

T;T;T;T

Sift4G

Benign

0.87

T;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.051

MVP

0.32

MPC

0.055

ClinPred

0.000014

GERP RS

0.22

PromoterAI

0.013

Neutral

(source)

Varity_R

0.023

gMVP

0.28

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over