chr12-53269289-C-T

Variant names:

• chr12-53269289-C-T
• rs2364600
• NM_012291.5:c.347C>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_012291.5(ESPL1):​c.347C>T​(p.Ala116Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00673 in 1,614,154 control chromosomes in the GnomAD database, including 620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.035 (295 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (325 hom.)
• Consequence: ESPL1 NM_012291.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.55

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018171072).
• BP6: Variant 12-53269289-C-T is Benign according to our data. Variant chr12-53269289-C-T is described in ClinVar as [Benign]. Clinvar id is 3056449.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESPL1	NM_012291.5	c.347C>T	p.Ala116Val	missense_variant	Exon 3 of 31	ENST00000257934.9	NP_036423.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESPL1	ENST00000257934.9	c.347C>T	p.Ala116Val	missense_variant	Exon 3 of 31	5	NM_012291.5	ENSP00000257934.4
ESPL1	ENST00000553219.6	c.347C>T	p.Ala116Val	missense_variant	Exon 3 of 3	2		ENSP00000456450.2
ESPL1	ENST00000552671.5	n.*278C>T		non_coding_transcript_exon_variant	Exon 3 of 31	2		ENSP00000447054.1
ESPL1	ENST00000552671.5	n.*278C>T		3_prime_UTR_variant	Exon 3 of 31	2		ENSP00000447054.1

Frequencies

GnomAD3 genomes AF: 0.0351 AC: 5341 AN: 152192 Hom.: 296 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.0210

GnomAD3 exomes AF: 0.00923 AC: 2320 AN: 251250 Hom.: 137 AF XY: 0.00682 AC XY: 926 AN XY: 135820

Gnomad AFR exome AF: 0.126

Gnomad AMR exome AF: 0.00567

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000379

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00377 AC: 5518 AN: 1461842 Hom.: 325 Cov.: 34 AF XY: 0.00324 AC XY: 2354 AN XY: 727216

Gnomad4 AFR exome AF: 0.132

Gnomad4 AMR exome AF: 0.00675

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000237

Gnomad4 OTH exome AF: 0.00791

GnomAD4 genome AF: 0.0351 AC: 5348 AN: 152312 Hom.: 295 Cov.: 32 AF XY: 0.0347 AC XY: 2587 AN XY: 74470

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.0137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000367

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.00695 Hom.: 129

Bravo AF: 0.0400

ESP6500AA AF: 0.119 AC: 523

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0112 AC: 1362

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ESPL1-related disorder Benign:1

Jun 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.80	T;T;.
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	.;M;M
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.1	D;N;N
REVEL	Benign	0.043
Sift	Benign	0.075	T;T;T
Sift4G	Uncertain	0.029	D;D;D
Polyphen		0.78	.;P;P
Vest4		0.26, 0.15
MPC		1.1
ClinPred		0.022	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.067
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2364600; hg19: chr12-53663073;