12-53269139-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_012291.5(ESPL1):c.197C>T(p.Ala66Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ESPL1 NM_012291.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.159

Genes affected

ESPL1 (HGNC:16856): (extra spindle pole bodies like 1, separase) Stable cohesion between sister chromatids before anaphase and their timely separation during anaphase are critical for chromosome inheritance. In vertebrates, sister chromatid cohesion is released in 2 steps via distinct mechanisms. The first step involves phosphorylation of STAG1 (MIM 604358) or STAG2 (MIM 300826) in the cohesin complex. The second step involves cleavage of the cohesin subunit SCC1 (RAD21; MIM 606462) by ESPL1, or separase, which initiates the final separation of sister chromatids (Sun et al., 2009 [PubMed 19345191]).[supplied by OMIM, Nov 2010]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ESPL1
• BP4: Computational evidence support a benign effect (MetaRNN=0.031185806).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESPL1	NM_012291.5	c.197C>T	p.Ala66Val	missense_variant	3/31	ENST00000257934.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESPL1	ENST00000257934.9	c.197C>T	p.Ala66Val	missense_variant	3/31	5	NM_012291.5	P1
ESPL1	ENST00000553219.6	c.197C>T	p.Ala66Val	missense_variant	3/3	2
ESPL1	ENST00000552671.5	c.*128C>T		3_prime_UTR_variant, NMD_transcript_variant	3/31	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461852 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Dec 15, 2023

The c.197C>T (p.A66V) alteration is located in exon 3 (coding exon 2) of the ESPL1 gene. This alteration results from a C to T substitution at nucleotide position 197, causing the alanine (A) at amino acid position 66 to be replaced by a valine (V). 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	0.099
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	14
Dann	Benign	0.94
DEOGEN2	Benign	0.032	T;T;T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.65	T;T;.
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.031	T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.2	N;N;N
Sift	Benign	0.29	T;T;T
Sift4G	Benign	0.57	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.064, 0.063
MutPred		0.28		Gain of catalytic residue at P68 (P = 0.0061);Gain of catalytic residue at P68 (P = 0.0061);Gain of catalytic residue at P68 (P = 0.0061);
MVP		0.22
MPC		0.65
ClinPred		0.064	T
GERP RS		1.8
Varity_R		0.048
gMVP		0.10

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: rs1943620132; hg19: chr12-53662923;