1-100273398-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

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

Scores

10
5
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.08
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

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

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RTCANM_003729.4 linkc.419T>C p.Phe140Ser missense_variant Exon 5 of 11 ENST00000370128.9 NP_003720.1 O00442-1
RTCANM_001130841.2 linkc.458T>C p.Phe153Ser missense_variant Exon 6 of 12 NP_001124313.1 O00442-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RTCAENST00000370128.9 linkc.419T>C p.Phe140Ser missense_variant Exon 5 of 11 1 NM_003729.4 ENSP00000359146.4 O00442-1
RTCAENST00000260563.4 linkc.458T>C p.Phe153Ser missense_variant Exon 6 of 12 1 ENSP00000260563.4 O00442-2
RTCAENST00000483474.1 linkn.629T>C non_coding_transcript_exon_variant Exon 6 of 6 3
RTCAENST00000498617.5 linkn.657T>C non_coding_transcript_exon_variant Exon 5 of 6 5

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152216
Hom.:
0
Cov.:
33
show subpopulations
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
show subpopulations
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000459
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152216
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74368
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 21, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.458T>C (p.F153S) alteration is located in exon 6 (coding exon 6) of the RTCA gene. This alteration results from a T to C substitution at nucleotide position 458, causing the phenylalanine (F) at amino acid position 153 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
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;T
M_CAP
Benign
0.020
T
MetaRNN
Pathogenic
0.83
D;D
MetaSVM
Uncertain
-0.13
T
MutationAssessor
Pathogenic
3.6
H;.
PrimateAI
Uncertain
0.64
T
PROVEAN
Pathogenic
-6.9
D;D
REVEL
Uncertain
0.58
Sift
Uncertain
0.0010
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
0.65
P;D
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

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1329565020; hg19: chr1-100738954; API