X-110450715-C-A

Position:

• chrX-110450715-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001385449.1(RTL9):​c.98C>A​(p.Thr33Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000638 in 1,097,496 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000064 (0 hom. 3 hem.)
• Consequence: RTL9 NM_001385449.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.215

Genes affected

RTL9 (HGNC:29245): (retrotransposon Gag like 9)

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10338041).
• BS2: High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTL9	NM_001385449.1	c.98C>A	p.Thr33Lys	missense_variant	3/4	ENST00000520821.6	NP_001372378.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTL9	ENST00000520821.6	c.98C>A	p.Thr33Lys	missense_variant	3/4	4	NM_001385449.1	ENSP00000430395.2
RTL9	ENST00000465301.2	c.98C>A	p.Thr33Lys	missense_variant	3/4	1		ENSP00000419786.2
RTL9	ENST00000540313.1	c.98C>A	p.Thr33Lys	missense_variant	1/2	2		ENSP00000441452.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000638 AC: 7 AN: 1097496 Hom.: 0 Cov.: 30 AF XY: 0.00000827 AC XY: 3 AN XY: 362858

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: 0.0000554

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000868

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2024

The c.98C>A (p.T33K) alteration is located in exon 3 (coding exon 1) of the RGAG1 gene. This alteration results from a C to A substitution at nucleotide position 98, causing the threonine (T) at amino acid position 33 to be replaced by a lysine (K). 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	Benign	0.14
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	3.1
DANN	Benign	0.80
DEOGEN2	Benign	0.090	T;T;T
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.33	T;.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-4.4	D;N;N
REVEL	Benign	0.044
Sift	Benign	0.035	D;D;D
Sift4G	Benign	0.73	T;T;T
Polyphen		0.22	.;B;B
Vest4		0.23, 0.21
MutPred		0.43		Gain of ubiquitination at T33 (P = 0.0146);Gain of ubiquitination at T33 (P = 0.0146);Gain of ubiquitination at T33 (P = 0.0146);
MVP		0.068
MPC		0.073
ClinPred		0.15	T
GERP RS		2.0
Varity_R		0.12
gMVP		0.24

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: rs1388098365; hg19: chrX-109693943;