X-74591523-C-T

Position:

• chrX-74591523-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_016120.4(RLIM):​c.1792G>A​(p.Asp598Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: RLIM NM_016120.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.82

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 Pathogenic. Variant got 14 ACMG points.

• PM1: In a zinc_finger_region RING-type (size 41) in uniprot entity RNF12_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_016120.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905
• PP5: Variant X-74591523-C-T is Pathogenic according to our data. Variant chrX-74591523-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 585243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-74591523-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RLIM	NM_016120.4	c.1792G>A	p.Asp598Asn	missense_variant	4/4	ENST00000332687.11
RLIM	NM_183353.3	c.1792G>A	p.Asp598Asn	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RLIM	ENST00000332687.11	c.1792G>A	p.Asp598Asn	missense_variant	4/4	1	NM_016120.4	P1
RLIM	ENST00000349225.2	c.1792G>A	p.Asp598Asn	missense_variant	5/5	2		P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, X-linked 61 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 16, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 31, 2019	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 31, 2020

Published functional studies demonstrate a damaging effect (Frints et al., 2018); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29728705) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	-0.063	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.2	D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.025	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		1.0	D;D
Vest4		0.79
MutPred		0.65		Loss of catalytic residue at D598 (P = 0.0815);Loss of catalytic residue at D598 (P = 0.0815);
MVP		0.90
MPC		1.8
ClinPred		0.95	D
GERP RS		5.4
Varity_R		0.74
gMVP		0.93

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

LitVar

Other links and lift over

dbSNP: rs1569309460; hg19: chrX-73811358; COSMIC: COSV60325321;