X-72129943-C-G

Variant names:

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

Variant summary

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

The NM_001405151.1(RTL5):​c.1598G>C​(p.Arg533Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,797 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: RTL5 NM_001405151.1 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>C	p.Arg533Pro	missense	Exon 1 of 1	NP_001392080.1	Q5HYW3
	NHSL2	NM_001013627.3	MANE Select	c.281-2136C>G		intron	N/A	NP_001013649.2	Q5HYW2-1
	RTL5	NM_001024455.4		c.1598G>C	p.Arg533Pro	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>C	p.Arg533Pro	missense	Exon 1 of 1	ENSP00000476792.1	Q5HYW3
	NHSL2	ENST00000633930.2	TSL:5 MANE Select	c.281-2136C>G		intron	N/A	ENSP00000488668.1	Q5HYW2-1
	RTL5	ENST00000479991.1	TSL:1	n.1598G>C		non_coding_transcript_exon	Exon 1 of 2	ENSP00000418667.1	Q5HYW3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097797 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 363229

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.0000284 AC: 1 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: 0.00 AC: 0 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: 0.00 AC: 0 AN: 841785

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.0085	T
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0056	T
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.63
PrimateAI	Uncertain	0.50	T
Sift4G	Uncertain	0.045	D
Polyphen		0.98	D
Vest4		0.58
MutPred		0.21		Loss of helix (P = 0.0033)
MVP		0.092
ClinPred		0.40	T
GERP RS		3.2
Varity_R		0.20
gMVP		0.21
Mutation Taster		=91/9	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;