chr18-21573520-T-C

Position:

• chr18-21573520-T-C

Variant summary

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

The NM_052911.3(ESCO1):​c.1324A>G​(p.Lys442Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ESCO1 NM_052911.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43

Genes affected

ESCO1 (HGNC:24645): (establishment of sister chromatid cohesion N-acetyltransferase 1) Enables identical protein binding activity; peptide-lysine-N-acetyltransferase activity; and zinc ion binding activity. Involved in peptidyl-lysine acetylation; post-translational protein acetylation; and regulation of DNA replication. Located in chromatin. [provided by Alliance of Genome Resources, Apr 2022]

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=0.16722819).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESCO1	NM_052911.3	c.1324A>G	p.Lys442Glu	missense_variant	4/12	ENST00000269214.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESCO1	ENST00000269214.10	c.1324A>G	p.Lys442Glu	missense_variant	4/12	1	NM_052911.3	P1
ESCO1	ENST00000383276.1	c.1324A>G	p.Lys442Glu	missense_variant, NMD_transcript_variant	4/13	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461566 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727046

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: 0.0000166

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2024

The c.1324A>G (p.K442E) alteration is located in exon 4 (coding exon 1) of the ESCO1 gene. This alteration results from a A to G substitution at nucleotide position 1324, causing the lysine (K) at amino acid position 442 to be replaced by a glutamic acid (E). 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	0.084
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.096	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.096
Sift	Uncertain	0.012	D
Sift4G	Benign	0.17	T
Polyphen		0.027	B
Vest4		0.15
MutPred		0.30		Loss of ubiquitination at K442 (P = 0.0107);
MVP		0.37
MPC		0.040
ClinPred		0.22	T
GERP RS		4.6
Varity_R		0.12
gMVP		0.20

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: rs2038369718; hg19: chr18-19153481;