rs183714924

Variant names:

• chrX-72130403-C-T
• rs183714924
• ENST00000609883.3:c.1138G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000609883.3(RTL5):​c.1138G>A​(p.Glu380Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,173,012 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 44 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., 19 hem., cov: 22)
  • Exomes 𝑓: 0.000090 (0 hom. 25 hem.)
• Consequence: RTL5 ENST00000609883.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.101
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049708486).
• BS2: High Hemizygotes in GnomAd4 at 19 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHSL2	NM_001013627.3	c.281-1676C>T		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.1138G>A	p.Glu380Lys	missense_variant	Exon 1 of 1	6		ENSP00000476792.1
NHSL2	ENST00000633930.2	c.281-1676C>T		intron_variant	Intron 1 of 7	5	NM_001013627.3	ENSP00000488668.1

Frequencies

GnomAD3 genomes AF: 0.000773 AC: 85 AN: 109978 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00252

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000683

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: 0.00

Gnomad OTH AF: 0.00136

GnomAD2 exomes AF: 0.000115 AC: 17 AN: 147256 AF XY: 0.0000884

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.000130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000257

GnomAD4 exome AF: 0.0000903 AC: 96 AN: 1062985 Hom.: 0 Cov.: 32 AF XY: 0.0000740 AC XY: 25 AN XY: 338025

African (AFR) AF: 0.00312 AC: 80 AN: 25650

American (AMR) AF: 0.0000947 AC: 3 AN: 31689

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18878

East Asian (EAS) AF: 0.00 AC: 0 AN: 29412

South Asian (SAS) AF: 0.0000579 AC: 3 AN: 51784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39131

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4012

European-Non Finnish (NFE) AF: 0.00000245 AC: 2 AN: 817457

Other (OTH) AF: 0.000178 AC: 8 AN: 44972

GnomAD4 genome AF: 0.000763 AC: 84 AN: 110027 Hom.: 0 Cov.: 22 AF XY: 0.000589 AC XY: 19 AN XY: 32275

African (AFR) AF: 0.00249 AC: 75 AN: 30180

American (AMR) AF: 0.000682 AC: 7 AN: 10259

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2624

East Asian (EAS) AF: 0.00 AC: 0 AN: 3518

South Asian (SAS) AF: 0.00 AC: 0 AN: 2488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5871

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 213

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52705

Other (OTH) AF: 0.00135 AC: 2 AN: 1486

Alfa AF: 0.000490 Hom.: 4

Bravo AF: 0.000994

ESP6500AA AF: 0.00115 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000176 AC: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1138G>A (p.E380K) alteration is located in exon 1 (coding exon 1) of the RGAG4 gene. This alteration results from a G to A substitution at nucleotide position 1138, causing the glutamic acid (E) at amino acid position 380 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	0.084
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	10
DANN	Benign	0.97
DEOGEN2	Benign	0.0014	T
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.97	T
PhyloP100		0.10
PrimateAI	Benign	0.31	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.048
ClinPred		0.031	T
GERP RS		1.4
Varity_R		0.059
gMVP		0.24
Mutation Taster		=100/0	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: rs183714924; hg19: chrX-71350253;