ENST00000609883.3:c.1654C>T

Variant names:

• chrX-72129887-G-A
• rs769386611
• ENST00000609883.3:c.1654C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The ENST00000609883.3(RTL5):​c.1654C>T​(p.Arg552Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000804 in 1,207,043 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 35 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000086 (0 hom. 34 hem.)
• Consequence: RTL5 ENST00000609883.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.631
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.092077255).
• BP6: Variant X-72129887-G-A is Benign according to our data. Variant chrX-72129887-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2660896.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High Hemizygotes in GnomAdExome4 at 34 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHSL2	NM_001013627.3	c.281-2192G>A		intron_variant	Intron 1 of 7	ENST00000633930.2	NP_001013649.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTL5	ENST00000609883.3	c.1654C>T	p.Arg552Cys	missense_variant	Exon 1 of 1	6		ENSP00000476792.1
NHSL2	ENST00000633930.2	c.281-2192G>A		intron_variant	Intron 1 of 7	5	NM_001013627.3	ENSP00000488668.1

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 111845 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000326

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: 0.0000377

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000569 AC: 10 AN: 175797 AF XY: 0.0000643

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000149

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000765

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000858 AC: 94 AN: 1095198 Hom.: 0 Cov.: 29 AF XY: 0.0000942 AC XY: 34 AN XY: 361016

African (AFR) AF: 0.00 AC: 0 AN: 26376

American (AMR) AF: 0.000143 AC: 5 AN: 34954

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19180

East Asian (EAS) AF: 0.00 AC: 0 AN: 30198

South Asian (SAS) AF: 0.00 AC: 0 AN: 53653

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40360

Middle Eastern (MID) AF: 0.000486 AC: 2 AN: 4118

European-Non Finnish (NFE) AF: 0.0000940 AC: 79 AN: 840380

Other (OTH) AF: 0.000174 AC: 8 AN: 45979

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 111845 Hom.: 0 Cov.: 23 AF XY: 0.0000294 AC XY: 1 AN XY: 34009

African (AFR) AF: 0.0000326 AC: 1 AN: 30709

American (AMR) AF: 0.00 AC: 0 AN: 10680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3543

South Asian (SAS) AF: 0.00 AC: 0 AN: 2661

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6093

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000377 AC: 2 AN: 53074

Other (OTH) AF: 0.00 AC: 0 AN: 1507

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000745 AC: 9

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Dec 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1654C>T (p.R552C) alteration is located in exon 1 (coding exon 1) of the RGAG4 gene. This alteration results from a C to T substitution at nucleotide position 1654, causing the arginine (R) at amino acid position 552 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NHSL2: BS2; RTL5: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0033	T
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-0.96	T
PhyloP100		0.63
PrimateAI	Uncertain	0.69	T
Sift4G	Benign	0.20	T
Polyphen		0.10	B
Vest4		0.19
MutPred		0.40		Gain of catalytic residue at L553 (P = 0.0092);
MVP		0.20
ClinPred		0.048	T
GERP RS		1.8
Varity_R		0.071
gMVP		0.093
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs769386611; hg19: chrX-71349737; COSMIC: COSV65453888; COSMIC: COSV65453888;