chrX-72129877-G-A

Variant names:

• chrX-72129877-G-A
• rs776991863
• ENST00000609883.3:c.1664C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The ENST00000609883.3(RTL5):​c.1664C>T​(p.Pro555Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000274 in 1,204,538 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000027 (0 hom. 9 hem.)
• Consequence: RTL5 ENST00000609883.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.31
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32926142).
• BS2: High Hemizygotes in GnomAdExome4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHSL2	NM_001013627.3	c.281-2202G>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.1664C>T	p.Pro555Leu	missense_variant	Exon 1 of 1	6		ENSP00000476792.1
NHSL2	ENST00000633930.2	c.281-2202G>A		intron_variant	Intron 1 of 7	5	NM_001013627.3	ENSP00000488668.1

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 111774 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

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: 0.0000565

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000348 AC: 6 AN: 172643 AF XY: 0.0000168

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000779

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000275 AC: 30 AN: 1092764 Hom.: 0 Cov.: 29 AF XY: 0.0000251 AC XY: 9 AN XY: 359102

African (AFR) AF: 0.00 AC: 0 AN: 26350

American (AMR) AF: 0.00 AC: 0 AN: 34772

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19001

East Asian (EAS) AF: 0.00 AC: 0 AN: 30188

South Asian (SAS) AF: 0.00 AC: 0 AN: 53202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40225

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4100

European-Non Finnish (NFE) AF: 0.0000358 AC: 30 AN: 839061

Other (OTH) AF: 0.00 AC: 0 AN: 45865

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 111774 Hom.: 0 Cov.: 23 AF XY: 0.0000295 AC XY: 1 AN XY: 33940

African (AFR) AF: 0.00 AC: 0 AN: 30687

American (AMR) AF: 0.00 AC: 0 AN: 10661

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3524

South Asian (SAS) AF: 0.00 AC: 0 AN: 2659

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6086

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

European-Non Finnish (NFE) AF: 0.0000565 AC: 3 AN: 53062

Other (OTH) AF: 0.00 AC: 0 AN: 1513

Alfa AF: 0.000324 Hom.: 2

Bravo AF: 0.0000340

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1664C>T (p.P555L) 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 1664, causing the proline (P) at amino acid position 555 to be replaced by a leucine (L). 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	0.68
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0096	T
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.3
PrimateAI	Pathogenic	0.79	T
Sift4G	Pathogenic	0.0010	D
Polyphen		0.96	D
Vest4		0.70
MVP		0.076
ClinPred		0.14	T
GERP RS		3.0
Varity_R		0.20
gMVP		0.23
Mutation Taster		=99/1	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: rs776991863; hg19: chrX-71349727; COSMIC: COSV65454872; COSMIC: COSV65454872;