17-31852820-T-C

Variant names:

• chr17-31852820-T-C
• rs1293332599
• NM_018405.4:c.377A>G

Variant summary

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

The NM_018405.4(COPRS):​c.377A>G​(p.Asn126Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,312 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: 0.0000014 (0 hom.)
• Consequence: COPRS NM_018405.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.79

Genes affected

COPRS (HGNC:28848): (coordinator of PRMT5 and differentiation stimulator) Enables histone binding activity. Involved in histone H4-R3 methylation. Located in cytosol; nucleoplasm; and plasma membrane. [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=0.29200658).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COPRS	NM_018405.4	c.377A>G	p.Asn126Ser	missense_variant	Exon 3 of 4	ENST00000302362.11	NP_060875.2
COPRS	NM_001330176.2	c.341A>G	p.Asn114Ser	missense_variant	Exon 3 of 4		NP_001317105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COPRS	ENST00000302362.11	c.377A>G	p.Asn126Ser	missense_variant	Exon 3 of 4	1	NM_018405.4	ENSP00000304327.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460312 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726598

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

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

Jan 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.377A>G (p.N126S) alteration is located in exon 3 (coding exon 3) of the COPRS gene. This alteration results from a A to G substitution at nucleotide position 377, causing the asparagine (N) at amino acid position 126 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	Benign	0.14
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.4	M;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.6	D;D;.
REVEL	Benign	0.14
Sift	Benign	0.045	D;D;.
Sift4G	Uncertain	0.056	T;T;.
Polyphen		1.0	D;.;.
Vest4		0.43
MutPred		0.15		Gain of glycosylation at N126 (P = 0.0161);.;.;
MVP		0.38
MPC		0.44
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.17
gMVP		0.17

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: rs1293332599; hg19: chr17-30179839;