X-74591586-A-G

Variant names:

• chrX-74591586-A-G
• rs1569309484
• NM_016120.4:c.1729T>C

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 rank	MANE	Protein	UniProt
RLIM	NM_016120.4	c.1729T>C	p.Tyr577His	missense_variant	Exon 4 of 4	ENST00000332687.11	NP_057204.2
RLIM	NM_183353.3	c.1729T>C	p.Tyr577His	missense_variant	Exon 5 of 5		NP_899196.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RLIM	ENST00000332687.11	c.1729T>C	p.Tyr577His	missense_variant	Exon 4 of 4	1	NM_016120.4	ENSP00000328059.6
RLIM	ENST00000349225.2	c.1729T>C	p.Tyr577His	missense_variant	Exon 5 of 5	2		ENSP00000253571.3

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

Dec 05, 2018

Institute for Genomic Medicine, Nationwide Children's Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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
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;