X-74591523-C-T

Variant names:

• chrX-74591523-C-T
• rs1569309460
• NM_016120.4:c.1792G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. 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
• Publications: 1 publications found

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]

RLIM Gene-Disease associations (from GenCC):

• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: Illumina
• intellectual disability, X-linked 61

  Inheritance: XL Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Broad Center for Mendelian Genomics, G2P
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 585243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016120.4. 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
	RLIM	NM_016120.4	MANE Select	c.1792G>A	p.Asp598Asn	missense	Exon 4 of 4	NP_057204.2
	RLIM	NM_183353.3		c.1792G>A	p.Asp598Asn	missense	Exon 5 of 5	NP_899196.1	Q9NVW2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RLIM	ENST00000332687.11	TSL:1 MANE Select	c.1792G>A	p.Asp598Asn	missense	Exon 4 of 4	ENSP00000328059.6	Q9NVW2-1
	RLIM	ENST00000349225.2	TSL:2	c.1792G>A	p.Asp598Asn	missense	Exon 5 of 5	ENSP00000253571.3	Q9NVW2-1
	RLIM	ENST00000896517.1		c.1792G>A	p.Asp598Asn	missense	Exon 4 of 4	ENSP00000566576.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Intellectual disability, X-linked 61 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	-0.063	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.8
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.65		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
Mutation Taster		=4/96	disease causing (ClinVar)

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