X-74591807-G-A

Position:

• chrX-74591807-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016120.4(RLIM):​c.1508C>T​(p.Ser503Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,994 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: RLIM NM_016120.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.84

Genes affected

RLIM (HGNC:13429): (ring finger protein, LIM domain interacting) The protein encoded by this gene is a RING-H2 zinc finger protein. It has been shown to be an E3 ubiquitin protein ligase that targets LIM domain binding 1 (LDB1/CLIM), and causes proteasome-dependent degradation of LDB1. This protein and LDB1 are co-repressors of LHX1/LIM-1, a homeodomain transcription factor. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15140572).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RLIM	NM_016120.4	c.1508C>T	p.Ser503Leu	missense_variant	4/4	ENST00000332687.11
RLIM	NM_183353.3	c.1508C>T	p.Ser503Leu	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RLIM	ENST00000332687.11	c.1508C>T	p.Ser503Leu	missense_variant	4/4	1	NM_016120.4	P1
RLIM	ENST00000349225.2	c.1508C>T	p.Ser503Leu	missense_variant	5/5	2		P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097994 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363366

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, X-linked 61 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jul 16, 2023

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Tonne-Kalscheuer syndrome (MIM#300978). Functional studies have shown that one missense variant has decreased protein expression (PMID: 33953269). Other studies have also shown several missense variants cause reduced ubiquitination of the target protein, and in vivo studies have suggested LoF based on the inability of mutants to rescue the phenotype in animal models (PMIDs: 29728705, 33953269). (I) 0109 - This gene is associated with X-linked disease. Most affected patients are males, with females being mildly affected and showing evidence for highly skewed X inactivation (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. While all affected males had intellectual disability, they also had variable behavioural anomalies with or without congenital malformations (PMID: 29728705). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.17	T;T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.57	.;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.85	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.82	N;N
REVEL	Benign	0.12
Sift	Benign	0.52	T;T
Sift4G	Benign	0.37	T;T
Polyphen		0.0030	B;B
Vest4		0.43
MutPred		0.32		Loss of phosphorylation at S503 (P = 0.0015);Loss of phosphorylation at S503 (P = 0.0015);
MVP		0.60
MPC		0.66
ClinPred		0.15	T
GERP RS		1.7
Varity_R		0.10
gMVP		0.36

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-73811642;