chr20-13733780-G-A

Position:

• chr20-13733780-G-A

Variant summary

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

The NM_001276380.2(ESF1):​c.1891C>T​(p.Pro631Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,570 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ESF1 NM_001276380.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.86

Genes affected

ESF1 (HGNC:15898): (ESF1 nucleolar pre-rRNA processing protein homolog) Enables RNA binding activity. Predicted to be involved in rRNA processing. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESF1	NM_001276380.2	c.1891C>T	p.Pro631Ser	missense_variant	10/14	ENST00000617257.2	NP_001263309.1
ESF1	NM_016649.4	c.1891C>T	p.Pro631Ser	missense_variant	10/14		NP_057733.2
ESF1	XM_017027874.3	c.1891C>T	p.Pro631Ser	missense_variant	10/14		XP_016883363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESF1	ENST00000617257.2	c.1891C>T	p.Pro631Ser	missense_variant	10/14	5	NM_001276380.2	ENSP00000480783	P1
ESF1	ENST00000202816.5	c.1891C>T	p.Pro631Ser	missense_variant	10/14	5		ENSP00000202816	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460570 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726644

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Apr 20, 2023

The c.1891C>T (p.P631S) alteration is located in exon 10 (coding exon 9) of the ESF1 gene. This alteration results from a C to T substitution at nucleotide position 1891, causing the proline (P) at amino acid position 631 to be replaced by a serine (S). 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	Pathogenic	0.75
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.9	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-7.6	D;.
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.012	D;D
Polyphen		1.0	D;.
Vest4		0.53
MutPred		0.16		Gain of phosphorylation at P631 (P = 0.0248);.;
MVP		0.76
MPC		0.43
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.84
gMVP		0.26

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: rs933009780; hg19: chr20-13714427; COSMIC: COSV52522321;