rs1179287557

Variant names:

• chr20-57329943-G-T
• rs1179287557
• NM_012444.3:c.76G>T

Your query was ambiguous. Multiple possible variants found:

• chr20-57329943-G-T
• chr20-57329943-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012444.3(SPO11):​c.76G>T​(p.Ala26Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SPO11 NM_012444.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.900
• Publications: 0 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]

ENSG00000303497 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06481457).

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.76G>T	p.Ala26Ser	missense	Exon 1 of 13	NP_036576.1	Q9Y5K1-1
	SPO11	NM_198265.2		c.76G>T	p.Ala26Ser	missense	Exon 1 of 12	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.76G>T	p.Ala26Ser	missense	Exon 1 of 13	ENSP00000360310.3	Q9Y5K1-1
	SPO11	ENST00000345868.8	TSL:1	c.76G>T	p.Ala26Ser	missense	Exon 1 of 12	ENSP00000316034.4	Q9Y5K1-2
	SPO11	ENST00000371260.8	TSL:5	c.76G>T	p.Ala26Ser	missense	Exon 1 of 12	ENSP00000360307.4	Q5TCH7

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152252 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248230 AF XY: 0.00000742

Gnomad AFR exome AF: 0.00

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: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460834 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726748

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

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111774

Other (OTH) AF: 0.00 AC: 0 AN: 60356

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74386

African (AFR) AF: 0.00 AC: 0 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15290

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: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000594

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	0.075
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.26
DANN	Benign	0.85
DEOGEN2	Benign	0.059	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.90
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.076
Sift	Benign	0.37	T
Sift4G	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.090
MutPred		0.61		Gain of phosphorylation at A26 (P = 0.0152)
MVP		0.21
MPC		0.053
ClinPred		0.056	T
GERP RS		-4.0
PromoterAI		-0.014	Neutral
Varity_R		0.048
gMVP		0.35
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs1179287557; hg19: chr20-55904999;