X-74591586-A-G

Position:

• chrX-74591586-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_016120.4(RLIM):​c.1729T>C​(p.Tyr577His) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: RLIM NM_016120.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.89

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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant X-74591586-A-G is Pathogenic according to our data. Variant chrX-74591586-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 598940.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-74591586-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RLIM	NM_016120.4	c.1729T>C	p.Tyr577His	missense_variant	4/4	ENST00000332687.11	NP_057204.2
RLIM	NM_183353.3	c.1729T>C	p.Tyr577His	missense_variant	5/5		NP_899196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RLIM	ENST00000332687.11	c.1729T>C	p.Tyr577His	missense_variant	4/4	1	NM_016120.4	ENSP00000328059	P1
RLIM	ENST00000349225.2	c.1729T>C	p.Tyr577His	missense_variant	5/5	2		ENSP00000253571	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, X-linked 61 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Institute for Genomic Medicine, Nationwide Children's Hospital

Dec 05, 2018

The Tyr577His variant in RLIM was reported along with several other hemizygous missense mutations in males with a syndromic X-linked intellectual disability and behavioral disorder (Family E in Frints et al, 2018). This variant is not observed in large population cohorts such as gnomAD (Lek et al, 2016), and is predicted to be damaging by a majority of computational tools. The Tyr577His variant occurs in the C-terminal catalytic RING-H2 zinc finger domain of the protein; in vitro functional studies indicate that missense changes in this domain impair RLIM ubiquitin ligase activity (Frints et al, 2018). It segregates with disease in the observed family E consistent with X-linked recessive inheritance. We therefore interpret Tyr577His as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	.;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Pathogenic	3.4	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0070	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;D
Vest4		0.90
MutPred		0.81		Gain of disorder (P = 0.0362);Gain of disorder (P = 0.0362);
MVP		0.86
MPC		2.1
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.90
gMVP		0.94

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: rs1569309484; hg19: chrX-73811421;