20-13733818-A-G

Position:

• chr20-13733818-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001276380.2(ESF1):​c.1853T>C​(p.Met618Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ESF1 NM_001276380.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.20

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33214906).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESF1	NM_001276380.2	c.1853T>C	p.Met618Thr	missense_variant	10/14	ENST00000617257.2	NP_001263309.1
ESF1	NM_016649.4	c.1853T>C	p.Met618Thr	missense_variant	10/14		NP_057733.2
ESF1	XM_017027874.3	c.1853T>C	p.Met618Thr	missense_variant	10/14		XP_016883363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESF1	ENST00000617257.2	c.1853T>C	p.Met618Thr	missense_variant	10/14	5	NM_001276380.2	ENSP00000480783	P1
ESF1	ENST00000202816.5	c.1853T>C	p.Met618Thr	missense_variant	10/14	5		ENSP00000202816	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460114 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726406

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

May 17, 2023

The c.1853T>C (p.M618T) alteration is located in exon 10 (coding exon 9) of the ESF1 gene. This alteration results from a T to C substitution at nucleotide position 1853, causing the methionine (M) at amino acid position 618 to be replaced by a threonine (T). 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	0.72
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.9	D;.
REVEL	Benign	0.16
Sift	Benign	0.22	T;.
Sift4G	Benign	0.23	T;T
Polyphen		0.97	D;.
Vest4		0.49
MutPred		0.26		Gain of phosphorylation at M618 (P = 0.0267);.;
MVP		0.63
MPC		0.43
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.25
gMVP		0.23

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: rs2049959356; hg19: chr20-13714465;