X-141176730-C-A

Variant names:

• chrX-141176730-C-A
• rs782148167
• NM_012317.4:c.292G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_012317.4(LDOC1):​c.292G>T​(p.Gly98Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,097,978 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000012 (0 hom. 1 hem.)
• Consequence: LDOC1 NM_012317.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.02

Genes affected

LDOC1 (HGNC:6548): (LDOC1 regulator of NFKB signaling) The protein encoded by this gene contains a leucine zipper-like motif and a proline-rich region that shares marked similarity with an SH3-binding domain. The protein localizes to the nucleus and is down-regulated in some cancer cell lines. It is thought to regulate the transcriptional response mediated by the nuclear factor kappa B (NF-kappaB). The gene has been proposed as a tumor suppressor gene whose protein product may have an important role in the development and/or progression of some cancers. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDOC1	NM_012317.4	c.292G>T	p.Gly98Trp	missense_variant	Exon 1 of 1	ENST00000370526.5	NP_036449.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDOC1	ENST00000370526.5	c.292G>T	p.Gly98Trp	missense_variant	Exon 1 of 1	6	NM_012317.4	ENSP00000359557.2
LDOC1	ENST00000460721.1	n.124+163G>T		intron_variant	Intron 1 of 1	1
LDOC1	ENST00000670989.1	n.206+163G>T		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000549 AC: 1 AN: 182213 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67427

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000118 AC: 13 AN: 1097978 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363334

Gnomad4 AFR exome AF: 0.0000379

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: 0.0000143

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

not specified Uncertain:1

Jan 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.292G>T (p.G98W) alteration is located in exon 1 (coding exon 1) of the LDOC1 gene. This alteration results from a G to T substitution at nucleotide position 292, causing the glycine (G) at amino acid position 98 to be replaced by a tryptophan (W). 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	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.8	M
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.76		Gain of catalytic residue at L96 (P = 0.0063);
MVP		0.71
MPC		2.8
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.82
gMVP		0.99

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: rs782148167; hg19: chrX-140270915; COSMIC: COSV100983225; COSMIC: COSV100983225;