20-57329973-A-G

Position:

• chr20-57329973-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T36I) 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
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 Benign. Variant got -14 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 id is 785662.Status of the report is criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
SPO11	NM_012444.3	c.106A>G	p.Thr36Ala	missense_variant	1/13	ENST00000371263.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPO11	ENST00000371263.8	c.106A>G	p.Thr36Ala	missense_variant	1/13	1	NM_012444.3	P1
SPO11	ENST00000345868.8	c.106A>G	p.Thr36Ala	missense_variant	1/12	1
SPO11	ENST00000371260.8	c.106A>G	p.Thr36Ala	missense_variant	1/12	5
SPO11	ENST00000418127.5	c.40A>G	p.Thr14Ala	missense_variant	1/10	3

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 2995 AN: 152196 Hom.: 81 Cov.: 32

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

GnomAD3 exomes AF: 0.00532 AC: 1259 AN: 236762 Hom.: 44 AF XY: 0.00381 AC XY: 493 AN XY: 129410

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 SAS exome AF: 0.000134

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.: 30 AF XY: 0.00191 AC XY: 1383 AN XY: 724222

Gnomad4 AFR exome AF: 0.0758

Gnomad4 AMR exome AF: 0.00478

Gnomad4 ASJ exome AF: 0.0000769

Gnomad4 EAS exome AF: 0.0000758

Gnomad4 SAS exome AF: 0.000291

Gnomad4 FIN exome AF: 0.0000196

Gnomad4 NFE exome AF: 0.000168

Gnomad4 OTH exome AF: 0.00474

GnomAD4 genome AF: 0.0197 AC: 2998 AN: 152314 Hom.: 81 Cov.: 32 AF XY: 0.0190 AC XY: 1414 AN XY: 74482

Gnomad4 AFR AF: 0.0679

Gnomad4 AMR AF: 0.00856

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0119

Alfa AF: 0.00307 Hom.: 6

Bravo AF: 0.0235

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0645 AC: 284

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00624 AC: 757

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.49
DANN	Benign	0.34
DEOGEN2	Benign	0.057	T;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0062	N
LIST_S2	Benign	0.074	T;T;T;T
MetaRNN	Benign	0.0026	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.69	N;N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
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	T
GERP RS		0.22
Varity_R		0.023
gMVP		0.28

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;