chr1-100266617-G-T

Variant names:

• chr1-100266617-G-T
• rs1451805696
• NM_003729.4:c.139G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003729.4(RTCA):​c.139G>T​(p.Gly47Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,142 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: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RTCA NM_003729.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.05
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977

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.139G>T	p.Gly47Cys	missense	Exon 2 of 11	NP_003720.1	O00442-1
	RTCA	NM_001130841.2		c.139G>T	p.Gly47Cys	missense	Exon 2 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.139G>T	p.Gly47Cys	missense	Exon 2 of 11	ENSP00000359146.4	O00442-1
	RTCA	ENST00000260563.4	TSL:1	c.139G>T	p.Gly47Cys	missense	Exon 2 of 12	ENSP00000260563.4	O00442-2
	RTCA	ENST00000370126.1	TSL:1	c.139G>T	p.Gly47Cys	missense	Exon 2 of 2	ENSP00000359144.1	A6NIC1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459142 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725530

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39600

South Asian (SAS) AF: 0.00 AC: 0 AN: 85926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110452

Other (OTH) AF: 0.00 AC: 0 AN: 60230

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 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	0.98
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		7.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-9.0	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.92		Loss of disorder (P = 0.034)
MVP		0.49
MPC		0.56
ClinPred		1.0	D
GERP RS		5.0
PromoterAI		-0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.93
Mutation Taster		=14/86	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: rs1451805696; hg19: chr1-100732173;