21-46302057-G-A

Variant names:

• chr21-46302057-G-A
• rs985859444
• NM_058180.5:c.911C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_058180.5(C21orf58):​c.911C>T​(p.Pro304Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 1,536,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000087 (0 hom.)
• Consequence: C21orf58 NM_058180.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.782
• Publications: 0 publications found

Genes affected

C21orf58 (HGNC:1300): (chromosome 21 open reading frame 58)

YBEY (HGNC:1299): (ybeY metalloendoribonuclease) This gene encodes a highly conserved metalloprotein. A similar protein in bacteria acts as an endoribonuclease, and is thought to function in ribosomal RNA maturation and ribosome assembly. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054526895).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C21orf58	NM_058180.5	c.911C>T	p.Pro304Leu	missense_variant	Exon 8 of 8	ENST00000291691.12	NP_478060.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C21orf58	ENST00000291691.12	c.911C>T	p.Pro304Leu	missense_variant	Exon 8 of 8	2	NM_058180.5	ENSP00000291691.8

Frequencies

GnomAD3 genomes AF: 0.0000267 AC: 4 AN: 149626 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000975

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000774 AC: 1 AN: 129166 AF XY: 0.00

Gnomad AFR exome AF: 0.000150

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000866 AC: 12 AN: 1386376 Hom.: 0 Cov.: 35 AF XY: 0.0000102 AC XY: 7 AN XY: 683178

African (AFR) AF: 0.000161 AC: 5 AN: 31116

American (AMR) AF: 0.00 AC: 0 AN: 34788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24848

East Asian (EAS) AF: 0.00 AC: 0 AN: 35004

South Asian (SAS) AF: 0.00 AC: 0 AN: 78486

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5646

European-Non Finnish (NFE) AF: 0.00000652 AC: 7 AN: 1073750

Other (OTH) AF: 0.00 AC: 0 AN: 57480

GnomAD4 genome AF: 0.0000267 AC: 4 AN: 149626 Hom.: 0 Cov.: 34 AF XY: 0.0000274 AC XY: 2 AN XY: 72890

African (AFR) AF: 0.0000975 AC: 4 AN: 41006

American (AMR) AF: 0.00 AC: 0 AN: 14668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5088

South Asian (SAS) AF: 0.00 AC: 0 AN: 4682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67138

Other (OTH) AF: 0.00 AC: 0 AN: 2052

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.911C>T (p.P304L) alteration is located in exon 8 (coding exon 8) of the C21orf58 gene. This alteration results from a C to T substitution at nucleotide position 911, causing the proline (P) at amino acid position 304 to be replaced by a leucine (L). 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	0.094
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	12
DANN	Benign	0.58
DEOGEN2	Benign	0.16	.;.;.;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.55	.;T;.;T;.;T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.055	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;.;.;N;.;.
PhyloP100		0.78
PROVEAN	Uncertain	-2.5	N;N;N;N;N;N
REVEL	Benign	0.020
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Benign	0.21	T;T;T;T;T;T
Polyphen		0.0020	.;.;.;B;.;.
Vest4		0.15
MutPred		0.23		.;.;.;Loss of relative solvent accessibility (P = 0.0071);.;.;
MVP		0.085
MPC		0.066
ClinPred		0.046	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.052
gMVP		0.35
Mutation Taster		=93/7	polymorphism

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: rs985859444; hg19: chr21-47721971;