20-57342817-T-C

Variant summary

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

The NM_012444.3(SPO11):c.1048T>C(p.Cys350Arg) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPO11 NM_012444.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08641118).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPO11	NM_012444.3	c.1048T>C	p.Cys350Arg	missense_variant	12/13	ENST00000371263.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPO11	ENST00000371263.8	c.1048T>C	p.Cys350Arg	missense_variant	12/13	1	NM_012444.3	P1
SPO11	ENST00000345868.8	c.934T>C	p.Cys312Arg	missense_variant	11/12	1
SPO11	ENST00000371260.8	c.922T>C	p.Cys308Arg	missense_variant	11/12	5
SPO11	ENST00000494972.1	c.*84T>C		3_prime_UTR_variant, NMD_transcript_variant	6/7	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2023

The c.1048T>C (p.C350R) alteration is located in exon 12 (coding exon 12) of the SPO11 gene. This alteration results from a T to C substitution at nucleotide position 1048, causing the cysteine (C) at amino acid position 350 to be replaced by an arginine (R). 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	0.091
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	15
Dann	Benign	0.87
DEOGEN2	Benign	0.050	T;.;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.55	T;T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.086	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.46	N;N;N
REVEL	Benign	0.016
Sift	Benign	0.47	T;T;T
Sift4G	Benign	0.36	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.25
MutPred		0.43		Gain of solvent accessibility (P = 0.0055);.;.;
MVP		0.28
MPC		0.094
ClinPred		0.10	T
GERP RS		1.5
Varity_R		0.091
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-55917873;