X-72130606-C-G

Position:

• chrX-72130606-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001024455.4(RTL5):​c.935G>C​(p.Arg312Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,051 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: RTL5 NM_001024455.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59

Genes affected

RTL5 (HGNC:29430): (retrotransposon Gag like 5)

NHSL2 (HGNC:33737): (NHS like 2) Predicted to enable calcium ion binding activity. Predicted to be involved in cell differentiation. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2606508).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTL5	NM_001405151.1	c.935G>C	p.Arg312Pro	missense_variant	1/1	ENST00000609883.3
RTL5	NM_001024455.4	c.935G>C	p.Arg312Pro	missense_variant	1/2
NHSL2	NM_001013627.3	c.281-1473C>G		intron_variant		ENST00000633930.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTL5	ENST00000609883.3	c.935G>C	p.Arg312Pro	missense_variant	1/1		NM_001405151.1	P1
NHSL2	ENST00000633930.2	c.281-1473C>G		intron_variant		5	NM_001013627.3	P3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098051 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 363477

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: 0.00

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 22

Bravo AF: 0.0000113

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

Jun 30, 2022

The c.935G>C (p.R312P) alteration is located in exon 1 (coding exon 1) of the RGAG4 gene. This alteration results from a G to C substitution at nucleotide position 935, causing the arginine (R) at amino acid position 312 to be replaced by a proline (P). 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	0.62
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.073	T
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.41	T
Sift4G	Pathogenic	0.0010	D
Polyphen		0.98	D
Vest4		0.37
MutPred		0.46		Gain of methylation at K315 (P = 0.0432);
MVP		0.19
ClinPred		0.87	D
GERP RS		3.3
Varity_R		0.67
gMVP		0.75

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: rs903596881; hg19: chrX-71350456;