chr20-57331862-T-C

Variant names:

• chr20-57331862-T-C
• rs2066453974
• NM_012444.3:c.161T>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012444.3(SPO11):​c.161T>C​(p.Ile54Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPO11 NM_012444.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.17

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34747553).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPO11	NM_012444.3	c.161T>C	p.Ile54Thr	missense_variant	Exon 2 of 13	ENST00000371263.8	NP_036576.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPO11	ENST00000371263.8	c.161T>C	p.Ile54Thr	missense_variant	Exon 2 of 13	1	NM_012444.3	ENSP00000360310.3
SPO11	ENST00000345868.8	c.132-1326T>C		intron_variant	Intron 1 of 11	1		ENSP00000316034.4
SPO11	ENST00000418127.5	c.95T>C	p.Ile32Thr	missense_variant	Exon 2 of 10	3		ENSP00000413185.1
SPO11	ENST00000371260.8	c.132-1326T>C		intron_variant	Intron 1 of 11	5		ENSP00000360307.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1446950 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 719566

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.161T>C (p.I54T) alteration is located in exon 2 (coding exon 2) of the SPO11 gene. This alteration results from a T to C substitution at nucleotide position 161, causing the isoleucine (I) at amino acid position 54 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.60	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.11
Sift	Benign	0.041	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.18	B;.
Vest4		0.47
MutPred		0.71		Loss of stability (P = 0.0051);.;
MVP		0.41
MPC		0.070
ClinPred		0.62	D
GERP RS		4.3
Varity_R		0.11
gMVP		0.65

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: rs2066453974; hg19: chr20-55906918; COSMIC: COSV100625674; COSMIC: COSV100625674;