20-57329973-A-T

Position:

• chr20-57329973-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012444.3(SPO11):​c.106A>T​(p.Thr36Ser) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T36A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPO11 NM_012444.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060759157).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPO11	NM_012444.3	c.106A>T	p.Thr36Ser	missense_variant	1/13	ENST00000371263.8	NP_036576.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPO11	ENST00000371263.8	c.106A>T	p.Thr36Ser	missense_variant	1/13	1	NM_012444.3	ENSP00000360310.3
SPO11	ENST00000345868.8	c.106A>T	p.Thr36Ser	missense_variant	1/12	1		ENSP00000316034.4
SPO11	ENST00000371260.8	c.106A>T	p.Thr36Ser	missense_variant	1/12	5		ENSP00000360307.4
SPO11	ENST00000418127.5	c.40A>T	p.Thr14Ser	missense_variant	1/10	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	0.065
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.22
DANN	Benign	0.42
DEOGEN2	Benign	0.049	T;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.046	T;T;T;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.061	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N;N;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.30	N;N;N;N
REVEL	Benign	0.065
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.85	T;T;T;T
Polyphen		0.0	B;B;.;.
Vest4		0.099
MutPred		0.24		Gain of MoRF binding (P = 0.1321);Gain of MoRF binding (P = 0.1321);Gain of MoRF binding (P = 0.1321);.;
MVP		0.39
MPC		0.052
ClinPred		0.055	T
GERP RS		0.22
Varity_R		0.026
gMVP		0.23

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;