1-100268164-A-T

Variant names:

• chr1-100268164-A-T
• rs1163231720
• NM_003729.4:c.159A>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003729.4(RTCA):​c.159A>T​(p.Leu53Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: RTCA NM_003729.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.914

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTCA	NM_003729.4	c.159A>T	p.Leu53Phe	missense_variant	Exon 3 of 11	ENST00000370128.9	NP_003720.1
RTCA	NM_001130841.2	c.198A>T	p.Leu66Phe	missense_variant	Exon 4 of 12		NP_001124313.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTCA	ENST00000370128.9	c.159A>T	p.Leu53Phe	missense_variant	Exon 3 of 11	1	NM_003729.4	ENSP00000359146.4
RTCA	ENST00000260563.4	c.198A>T	p.Leu66Phe	missense_variant	Exon 4 of 12	1		ENSP00000260563.4
RTCA	ENST00000483474.1	n.369A>T		non_coding_transcript_exon_variant	Exon 4 of 6	3
RTCA	ENST00000498617.5	n.397A>T		non_coding_transcript_exon_variant	Exon 3 of 6	5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74340

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Pathogenic	3.9	H;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.026	D;D
Sift4G	Uncertain	0.050	T;T
Polyphen		0.97	D;D
Vest4		0.74
MutPred		0.86		Loss of disorder (P = 0.0887);.;
MVP		0.62
MPC		0.49
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.38
gMVP		0.70

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: rs1163231720; hg19: chr1-100733720;