rs761235091

Variant names:

• chr20-57331870-G-A
• rs761235091
• NM_012444.3:c.169G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-57331870-G-A
• chr20-57331870-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_012444.3(SPO11):​c.169G>A​(p.Asp57Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000436 in 1,606,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SPO11 NM_012444.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.67
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.169G>A	p.Asp57Asn	missense	Exon 2 of 13	NP_036576.1	Q9Y5K1-1
	SPO11	NM_198265.2		c.132-1318G>A		intron	N/A	NP_937998.1	Q9Y5K1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPO11	ENST00000371263.8	TSL:1 MANE Select	c.169G>A	p.Asp57Asn	missense	Exon 2 of 13	ENSP00000360310.3	Q9Y5K1-1
	SPO11	ENST00000345868.8	TSL:1	c.132-1318G>A		intron	N/A	ENSP00000316034.4	Q9Y5K1-2
	SPO11	ENST00000418127.5	TSL:3	c.103G>A	p.Asp35Asn	missense	Exon 2 of 10	ENSP00000413185.1	Q5TCH6

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152052 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

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: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248042 AF XY: 0.00

Gnomad AFR exome AF: 0.0000622

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: 0.00000138 AC: 2 AN: 1453994 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 723244

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000602 AC: 2 AN: 33218

American (AMR) AF: 0.00 AC: 0 AN: 43902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25944

East Asian (EAS) AF: 0.00 AC: 0 AN: 39366

South Asian (SAS) AF: 0.00 AC: 0 AN: 84488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108170

Other (OTH) AF: 0.00 AC: 0 AN: 60042

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152052 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74298

African (AFR) AF: 0.000121 AC: 5 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.7
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.034
Sift	Benign	0.50	T
Sift4G	Benign	0.39	T
Polyphen		0.0030	B
Vest4		0.27
MutPred		0.32		Loss of catalytic residue at D57 (P = 0.0842)
MVP		0.38
MPC		0.058
ClinPred		0.052	T
GERP RS		3.5
Varity_R		0.057
gMVP		0.46
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.46		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.46		Position offset: -37

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs761235091; hg19: chr20-55906926;