1-100274913-G-A

Variant names:

• chr1-100274913-G-A
• rs201888973
• NM_003729.4:c.563G>A

Variant summary

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

The NM_003729.4(RTCA):​c.563G>A​(p.Cys188Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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: 0.0000027 (0 hom.)
• Consequence: RTCA NM_003729.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.550
• Publications: 1 publications found

Genes affected

RTCA (HGNC:17981): (RNA 3'-terminal phosphate cyclase) This gene encodes a member of the RNA 3'-phosphate cyclase family. The encoded protein plays a role in RNA metabolism by catalyzing the ATP-dependent conversion of the 3'-phosphate of RNA substrates to a 2',3'-cyclic phosphodiester. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Feb 2012]

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=0.06601453).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003729.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTCA	NM_003729.4	MANE Select	c.563G>A	p.Cys188Tyr	missense	Exon 6 of 11	NP_003720.1	O00442-1
	RTCA	NM_001130841.2		c.602G>A	p.Cys201Tyr	missense	Exon 7 of 12	NP_001124313.1	O00442-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTCA	ENST00000370128.9	TSL:1 MANE Select	c.563G>A	p.Cys188Tyr	missense	Exon 6 of 11	ENSP00000359146.4	O00442-1
	RTCA	ENST00000260563.4	TSL:1	c.602G>A	p.Cys201Tyr	missense	Exon 7 of 12	ENSP00000260563.4	O00442-2
	RTCA	ENST00000881959.1		c.563G>A	p.Cys188Tyr	missense	Exon 6 of 12	ENSP00000552018.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460776 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726696

African (AFR) AF: 0.000120 AC: 4 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111260

Other (OTH) AF: 0.00 AC: 0 AN: 60322

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Benign	0.63
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.55
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.028
Sift	Benign	0.050	D
Sift4G	Uncertain	0.032	D
Polyphen		0.0040	B
Vest4		0.23
MVP		0.17
MPC		0.19
ClinPred		0.56	D
GERP RS		2.5
Varity_R		0.062
gMVP		0.66
Mutation Taster		=98/2	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: rs201888973; hg19: chr1-100740469;