X-72129958-G-C

Position:

• chrX-72129958-G-C

Variant summary

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

The NM_001024455.4(RTL5):​c.1583C>G​(p.Ser528Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: RTL5 NM_001024455.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.12

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3038424).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHSL2	NM_001013627.3	c.281-2121G>C		intron_variant		ENST00000633930.2	NP_001013649.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTL5	ENST00000609883.3	c.1583C>G	p.Ser528Cys	missense_variant	1/1	6		ENSP00000476792.1
NHSL2	ENST00000633930.2	c.281-2121G>C		intron_variant		5	NM_001013627.3	ENSP00000488668.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000378

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

Nov 08, 2022

The c.1583C>G (p.S528C) alteration is located in exon 1 (coding exon 1) of the RGAG4 gene. This alteration results from a C to G substitution at nucleotide position 1583, causing the serine (S) at amino acid position 528 to be replaced by a cysteine (C). 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	0.17
BayesDel_addAF	Benign	-0.0067	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.010	T
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.61	T
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.47
MutPred		0.17		Loss of phosphorylation at S528 (P = 0.0564);
MVP		0.076
ClinPred		0.35	T
GERP RS		4.1
Varity_R		0.15
gMVP		0.37

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: rs2042269262; hg19: chrX-71349808;