1-100270678-A-T

Variant names:

• chr1-100270678-A-T
• rs752820408
• NM_003729.4:c.412A>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003729.4(RTCA):​c.412A>T​(p.Met138Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RTCA NM_003729.4 missense, splice_region
• Scores: Splicing: ADA: 0.1266
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.83

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27999866).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTCA	NM_003729.4	c.412A>T	p.Met138Leu	missense_variant, splice_region_variant	Exon 4 of 11	ENST00000370128.9	NP_003720.1
RTCA	NM_001130841.2	c.451A>T	p.Met151Leu	missense_variant, splice_region_variant	Exon 5 of 12		NP_001124313.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTCA	ENST00000370128.9	c.412A>T	p.Met138Leu	missense_variant, splice_region_variant	Exon 4 of 11	1	NM_003729.4	ENSP00000359146.4
RTCA	ENST00000260563.4	c.451A>T	p.Met151Leu	missense_variant, splice_region_variant	Exon 5 of 12	1		ENSP00000260563.4
RTCA	ENST00000483474.1	n.622A>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 6	3
RTCA	ENST00000498617.5	n.650A>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461264 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726938

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Benign	0.89
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.14
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.17
Sift	Benign	0.16	T;T
Sift4G	Benign	0.38	T;T
Polyphen		0.0060	B;B
Vest4		0.40
MutPred		0.55		Gain of catalytic residue at M138 (P = 0.0329);.;
MVP		0.30
MPC		0.10
ClinPred		0.16	T
GERP RS		5.5
Varity_R		0.28
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.13
dbscSNV1_RF	Benign	0.27
SpliceAI score (max)		0.17		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: rs752820408; hg19: chr1-100736234;