X-72129943-C-T

Variant names:

• chrX-72129943-C-T
• rs930832925
• NM_001405151.1:c.1598G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001405151.1(RTL5):​c.1598G>A​(p.Arg533His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,209,183 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R533C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: RTL5 NM_001405151.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.631
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08734807).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001405151.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTL5	NM_001405151.1	MANE Select	c.1598G>A	p.Arg533His	missense	Exon 1 of 1	NP_001392080.1	Q5HYW3
	NHSL2	NM_001013627.3	MANE Select	c.281-2136C>T		intron	N/A	NP_001013649.2	Q5HYW2-1
	RTL5	NM_001024455.4		c.1598G>A	p.Arg533His	missense	Exon 1 of 2	NP_001019626.1	Q5HYW3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTL5	ENST00000609883.3	TSL:6 MANE Select	c.1598G>A	p.Arg533His	missense	Exon 1 of 1	ENSP00000476792.1	Q5HYW3
	NHSL2	ENST00000633930.2	TSL:5 MANE Select	c.281-2136C>T		intron	N/A	ENSP00000488668.1	Q5HYW2-1
	RTL5	ENST00000479991.1	TSL:1	n.1598G>A		non_coding_transcript_exon	Exon 1 of 2	ENSP00000418667.1	Q5HYW3

Frequencies

GnomAD3 genomes AF: 0.0000359 AC: 4 AN: 111386 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000655

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: 0.0000378

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097797 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 1 AN XY: 363229

African (AFR) AF: 0.00 AC: 0 AN: 26397

American (AMR) AF: 0.00 AC: 0 AN: 35198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40509

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841785

Other (OTH) AF: 0.00 AC: 0 AN: 46072

GnomAD4 genome AF: 0.0000359 AC: 4 AN: 111386 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33590

African (AFR) AF: 0.0000655 AC: 2 AN: 30548

American (AMR) AF: 0.00 AC: 0 AN: 10658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2633

East Asian (EAS) AF: 0.00 AC: 0 AN: 3532

South Asian (SAS) AF: 0.00 AC: 0 AN: 2625

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000378 AC: 2 AN: 52965

Other (OTH) AF: 0.00 AC: 0 AN: 1503

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Benign	0.0034	T
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-0.98	T
PhyloP100		0.63
PrimateAI	Benign	0.48	T
Sift4G	Pathogenic	0.0010	D
Polyphen		0.013	B
Vest4		0.16
MutPred		0.26		Loss of MoRF binding (P = 0.0428)
MVP		0.11
ClinPred		0.13	T
GERP RS		3.2
Varity_R		0.035
gMVP		0.083
Mutation Taster		=95/5	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: rs930832925; hg19: chrX-71349793; COSMIC: COSV108906230; COSMIC: COSV108906230;