rs1329565020

Variant names:

• chr1-100273398-T-C
• rs1329565020
• NM_003729.4:c.419T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003729.4(RTCA):​c.419T>C​(p.Phe140Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000443 in 1,578,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: RTCA NM_003729.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.08
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829

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.419T>C	p.Phe140Ser	missense	Exon 5 of 11	NP_003720.1	O00442-1
	RTCA	NM_001130841.2		c.458T>C	p.Phe153Ser	missense	Exon 6 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.419T>C	p.Phe140Ser	missense	Exon 5 of 11	ENSP00000359146.4	O00442-1
	RTCA	ENST00000260563.4	TSL:1	c.458T>C	p.Phe153Ser	missense	Exon 6 of 12	ENSP00000260563.4	O00442-2
	RTCA	ENST00000881959.1		c.419T>C	p.Phe140Ser	missense	Exon 5 of 12	ENSP00000552018.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000351 AC: 5 AN: 1426362 Hom.: 0 Cov.: 26 AF XY: 0.00000423 AC XY: 3 AN XY: 708832

African (AFR) AF: 0.00 AC: 0 AN: 32532

American (AMR) AF: 0.00 AC: 0 AN: 40694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25482

East Asian (EAS) AF: 0.00 AC: 0 AN: 39226

South Asian (SAS) AF: 0.00 AC: 0 AN: 81036

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00000459 AC: 5 AN: 1090336

Other (OTH) AF: 0.00 AC: 0 AN: 59096

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

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	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.65	P
Vest4		0.86
MutPred		0.65		Loss of methylation at K141 (P = 0.0331)
MVP		0.42
MPC		0.52
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.88
gMVP		0.95
Mutation Taster		=49/51	disease causing

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: rs1329565020; hg19: chr1-100738954;