X-74591520-G-A

Position:

• chrX-74591520-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_016120.4(RLIM):​c.1795C>T​(p.Arg599Cys) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: RLIM NM_016120.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.54

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 Likely_pathogenic. Variant got 7 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, 0.927
• PP5: Variant X-74591520-G-A is Pathogenic according to our data. Variant chrX-74591520-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 253089.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-74591520-G-A is described in Lovd as [Pathogenic]. Variant chrX-74591520-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RLIM	NM_016120.4	c.1795C>T	p.Arg599Cys	missense_variant	4/4	ENST00000332687.11
RLIM	NM_183353.3	c.1795C>T	p.Arg599Cys	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RLIM	ENST00000332687.11	c.1795C>T	p.Arg599Cys	missense_variant	4/4	1	NM_016120.4	P1
RLIM	ENST00000349225.2	c.1795C>T	p.Arg599Cys	missense_variant	5/5	2		P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, X-linked 61 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 11, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T;T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.0031	D
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.1	D;D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.71
MutPred		0.65		Gain of catalytic residue at W600 (P = 0.0059);Gain of catalytic residue at W600 (P = 0.0059);
MVP		0.93
MPC		2.1
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.93
gMVP		0.95

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: rs1569309459; hg19: chrX-73811355; COSMIC: COSV100222889;