NM_012444.3:c.40G>A

Variant names:

• chr20-57329907-G-A
• rs374455093
• NM_012444.3:c.40G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012444.3(SPO11):​c.40G>A​(p.Asp14Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPO11 NM_012444.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.426

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]

LOC105372687 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16547567).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPO11	NM_012444.3	c.40G>A	p.Asp14Asn	missense_variant	Exon 1 of 13	ENST00000371263.8	NP_036576.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPO11	ENST00000371263.8	c.40G>A	p.Asp14Asn	missense_variant	Exon 1 of 13	1	NM_012444.3	ENSP00000360310.3
SPO11	ENST00000345868.8	c.40G>A	p.Asp14Asn	missense_variant	Exon 1 of 12	1		ENSP00000316034.4
SPO11	ENST00000371260.8	c.40G>A	p.Asp14Asn	missense_variant	Exon 1 of 12	5		ENSP00000360307.4
SPO11	ENST00000418127.5	c.-27G>A		upstream_gene_variant		3		ENSP00000413185.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T;.;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.34	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.50	N;N;N
REVEL	Benign	0.055
Sift	Benign	0.26	T;D;T
Sift4G	Benign	0.44	T;T;T
Polyphen		0.092	B;B;.
Vest4		0.16
MutPred		0.67		Gain of catalytic residue at D14 (P = 0.0373);Gain of catalytic residue at D14 (P = 0.0373);Gain of catalytic residue at D14 (P = 0.0373);
MVP		0.64
MPC		0.060
ClinPred		0.083	T
GERP RS		0.0057
Varity_R		0.054
gMVP		0.39

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: rs374455093; hg19: chr20-55904963;