rs6580942

Variant names:

• chr12-53268840-C-A
• rs6580942
• NM_012291.5:c.74C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012291.5(ESPL1):​c.74C>A​(p.Ala25Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.716 in 1,608,306 control chromosomes in the GnomAD database, including 420,151 homozygotes. 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.

• Frequency:
  • Genomes: 𝑓 0.78 (47805 hom., cov: 31)
  • Exomes 𝑓: 0.71 (372346 hom.)
• Consequence: ESPL1 NM_012291.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.46
• Publications: 46 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.4797505E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESPL1	NM_012291.5	c.74C>A	p.Ala25Asp	missense_variant	Exon 2 of 31	ENST00000257934.9	NP_036423.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESPL1	ENST00000257934.9	c.74C>A	p.Ala25Asp	missense_variant	Exon 2 of 31	5	NM_012291.5	ENSP00000257934.4
ESPL1	ENST00000553219.6	c.74C>A	p.Ala25Asp	missense_variant	Exon 2 of 3	2		ENSP00000456450.2
ESPL1	ENST00000552671.5	n.74C>A		non_coding_transcript_exon_variant	Exon 2 of 31	2		ENSP00000447054.1

Frequencies

GnomAD3 genomes AF: 0.782 AC: 118847 AN: 151964 Hom.: 47740 Cov.: 31

Gnomad AFR AF: 0.947

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.796

Gnomad ASJ AF: 0.709

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.908

Gnomad FIN AF: 0.688

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.675

Gnomad OTH AF: 0.745

GnomAD2 exomes AF: 0.772 AC: 189898 AN: 245924 AF XY: 0.768

Gnomad AFR exome AF: 0.951

Gnomad AMR exome AF: 0.856

Gnomad ASJ exome AF: 0.725

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.686

Gnomad NFE exome AF: 0.674

Gnomad OTH exome AF: 0.738

GnomAD4 exome AF: 0.710 AC: 1033250 AN: 1456224 Hom.: 372346 Cov.: 36 AF XY: 0.713 AC XY: 516544 AN XY: 724178

African (AFR) AF: 0.955 AC: 31952 AN: 33442

American (AMR) AF: 0.850 AC: 37620 AN: 44236

Ashkenazi Jewish (ASJ) AF: 0.725 AC: 18895 AN: 26058

East Asian (EAS) AF: 0.999 AC: 39649 AN: 39686

South Asian (SAS) AF: 0.885 AC: 75815 AN: 85630

European-Finnish (FIN) AF: 0.686 AC: 36146 AN: 52692

Middle Eastern (MID) AF: 0.781 AC: 4495 AN: 5752

European-Non Finnish (NFE) AF: 0.671 AC: 744232 AN: 1108482

Other (OTH) AF: 0.738 AC: 44446 AN: 60246

GnomAD4 genome AF: 0.782 AC: 118971 AN: 152082 Hom.: 47805 Cov.: 31 AF XY: 0.786 AC XY: 58446 AN XY: 74320

African (AFR) AF: 0.947 AC: 39291 AN: 41504

American (AMR) AF: 0.796 AC: 12157 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.709 AC: 2456 AN: 3466

East Asian (EAS) AF: 0.997 AC: 5167 AN: 5184

South Asian (SAS) AF: 0.907 AC: 4367 AN: 4814

European-Finnish (FIN) AF: 0.688 AC: 7265 AN: 10564

Middle Eastern (MID) AF: 0.738 AC: 217 AN: 294

European-Non Finnish (NFE) AF: 0.675 AC: 45879 AN: 67966

Other (OTH) AF: 0.748 AC: 1580 AN: 2112

Alfa AF: 0.714 Hom.: 138974

Bravo AF: 0.794

TwinsUK AF: 0.665 AC: 2467

ALSPAC AF: 0.657 AC: 2533

ESP6500AA AF: 0.938 AC: 4135

ESP6500EA AF: 0.678 AC: 5835

ExAC AF: 0.770 AC: 93546

Asia WGS AF: 0.941 AC: 3268 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	16
DANN	Benign	0.73
DEOGEN2	Benign	0.0088	T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.29	T;T;.
MetaRNN	Benign	5.5e-7	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.5	.;N;N
PhyloP100		3.5
PrimateAI	Benign	0.39	T
PROVEAN	Benign	5.8	N;N;N
REVEL	Benign	0.10
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.077, 0.030
MPC		0.98
ClinPred		0.0059	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.085
gMVP		0.26
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6580942; hg19: chr12-53662624; COSMIC: COSV107243428;