dbSNP rs760192298: SPO11:p.Thr248Thr (chr20-57335907-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_012444.3(SPO11):c.744G>A(p.Thr248Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000637 in 1,569,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

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

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

SPO11
NM_012444.3 splice_region, synonymous

Scores

Splicing: ADA: 0.9998

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.75

Publications

0 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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 20-57335907-G-A is Pathogenic according to our data. Variant chr20-57335907-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1244233.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012444.3. 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
	SPO11	NM_012444.3	MANE Select	c.744G>A	p.Thr248Thr	splice_region synonymous	Exon 8 of 13	NP_036576.1	Q9Y5K1-1
	SPO11	NM_198265.2		c.630G>A	p.Thr210Thr	splice_region synonymous	Exon 7 of 12	NP_937998.1	Q9Y5K1-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPO11	ENST00000371263.8	TSL:1 MANE Select	c.744G>A	p.Thr248Thr	splice_region synonymous	Exon 8 of 13	ENSP00000360310.3	Q9Y5K1-1
SPO11	ENST00000345868.8	TSL:1	c.630G>A	p.Thr210Thr	splice_region synonymous	Exon 7 of 12	ENSP00000316034.4	Q9Y5K1-2
SPO11	ENST00000371260.8	TSL:5	c.618G>A	p.Thr206Thr	splice_region synonymous	Exon 7 of 12	ENSP00000360307.4	Q5TCH7

Frequencies

GnomAD3 genomes

AF:

0.0000265

AC:

AN:

151134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000731

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000210

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249484

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000619

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:

0.00000423

AC:

AN:

1418702

Hom.:

Cov.:

AF XY:

0.00000282

AC XY:

AN XY:

708454

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32542

American (AMR)

AF:

0.00

AC:

AN:

44316

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25862

East Asian (EAS)

AF:

0.00

AC:

AN:

39482

South Asian (SAS)

AF:

0.00

AC:

AN:

84874

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00000466

AC:

AN:

1073552

Other (OTH)

AF:

0.0000169

AC:

AN:

59010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000265

AC:

AN:

151134

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73698

show subpopulations

African (AFR)

AF:

0.0000731

AC:

AN:

41020

American (AMR)

AF:

0.00

AC:

AN:

15070

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000210

AC:

AN:

4772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67908

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000579

Hom.:

Bravo

AF:

0.0000189

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Non-obstructive azoospermia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.63

PhyloP100

2.8

Mutation Taster

=18/82

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.81

SpliceAI score (max)

0.52

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.52

Position offset: 0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over