X-74591451-T-C

Variant names:

• chrX-74591451-T-C
• NM_016120.4:c.1864A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016120.4(RLIM):​c.1864A>G​(p.Ser622Gly) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: RLIM NM_016120.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.43

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35023713).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RLIM	NM_016120.4	c.1864A>G	p.Ser622Gly	missense_variant	Exon 4 of 4	ENST00000332687.11	NP_057204.2
RLIM	NM_183353.3	c.1864A>G	p.Ser622Gly	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.1864A>G	p.Ser622Gly	missense_variant	Exon 4 of 4	1	NM_016120.4	ENSP00000328059.6
RLIM	ENST00000349225.2	c.1864A>G	p.Ser622Gly	missense_variant	Exon 5 of 5	2		ENSP00000253571.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000183 AC: 2 AN: 1093316 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 358994

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000239

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 29, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1864A>G (p.S622G) alteration is located in exon 5 (coding exon 3) of the RLIM gene. This alteration results from an A to G substitution at nucleotide position 1864, causing the serine (S) at amino acid position 622 to be replaced by a glycine (G). Based on data from the Genome Aggregation Database (gnomAD), the RLIM c.1864A>G alteration was not observed, with coverage at this position. This alteration has been reported de novo once from a cohort of fetuses with abnormalities detected on ultrasound. The affected fetus was reported with subependymal nodules in the left ventricle and mild left ventriculomegaly, but further clinical information was not provided (Qi, 2020). The p.S622 amino acid is highly conserved in available vertebrate species. The p.S622G alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.99	L;L
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.25
Sift	Benign	0.11	T;T
Sift4G	Uncertain	0.031	D;D
Polyphen		0.78	P;P
Vest4		0.56
MutPred		0.25		Loss of phosphorylation at S622 (P = 0.03);Loss of phosphorylation at S622 (P = 0.03);
MVP		0.61
MPC		1.5
ClinPred		0.85	D
GERP RS		5.4
Varity_R		0.52
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-73811286;