4-53508082-C-T

Variant names:

• chr4-53508082-C-T
• rs757156927
• NM_001126328.3:c.526G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001126328.3(LNX1):​c.526G>A​(p.Glu176Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: LNX1 NM_001126328.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.52
• Publications: 4 publications found

Genes affected

LNX1 (HGNC:6657): (ligand of numb-protein X 1) This gene encodes a membrane-bound protein that is involved in signal transduction and protein interactions. The encoded product is an E3 ubiquitin-protein ligase, which mediates ubiquitination and subsequent proteasomal degradation of proteins containing phosphotyrosine binding (PTB) domains. This protein may play an important role in tumorogenesis. Alternatively spliced transcript variants encoding distinct isoforms have been described. A pseudogene, which is located on chromosome 17, has been identified for this gene. [provided by RefSeq, Jul 2008]

ENSG00000282278 (HGNC:):

LNX1-AS1 (HGNC:40345): (LNX1 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001126328.3. 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
	LNX1	NM_001126328.3	MANE Select	c.526G>A	p.Glu176Lys	missense	Exon 3 of 11	NP_001119800.1	Q8TBB1-1
	LNX1	NM_032622.3		c.238G>A	p.Glu80Lys	missense	Exon 2 of 10	NP_116011.2	Q8TBB1-2
	LNX1-AS1	NR_046622.1		n.266+6106C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LNX1	ENST00000263925.8	TSL:1 MANE Select	c.526G>A	p.Glu176Lys	missense	Exon 3 of 11	ENSP00000263925.7	Q8TBB1-1
	LNX1	ENST00000306888.6	TSL:1	c.238G>A	p.Glu80Lys	missense	Exon 2 of 10	ENSP00000302879.2	Q8TBB1-2
	ENSG00000282278	ENST00000507166.5	TSL:2	c.1017+82117C>T		intron	N/A	ENSP00000423325.1	A0A0B4J203

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251078 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461866 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727234

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000789 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.5
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.099
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.021	D
Polyphen		0.78	P
Vest4		0.59
MutPred		0.28		Gain of ubiquitination at E176 (P = 0.0069)
MVP		0.43
MPC		0.088
ClinPred		0.52	D
GERP RS		4.5
Varity_R		0.22
gMVP		0.71
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs757156927; hg19: chr4-54374249; COSMIC: COSV55792145;