chr4-53478723-G-A

Position:

• chr4-53478723-G-A

Variant summary

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

The NM_001126328.3(LNX1):​c.1505C>T​(p.Thr502Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LNX1 NM_001126328.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.86

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:):

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=0.27359408).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LNX1	NM_001126328.3	c.1505C>T	p.Thr502Ile	missense_variant	8/11	ENST00000263925.8	NP_001119800.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LNX1	ENST00000263925.8	c.1505C>T	p.Thr502Ile	missense_variant	8/11	1	NM_001126328.3	ENSP00000263925.7
LNX1	ENST00000306888.6	c.1217C>T	p.Thr406Ile	missense_variant	7/10	1		ENSP00000302879.2
ENSG00000282278	ENST00000507166.5	c.1017+52758G>A		intron_variant		2		ENSP00000423325.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2024

The c.1505C>T (p.T502I) alteration is located in exon 8 (coding exon 7) of the LNX1 gene. This alteration results from a C to T substitution at nucleotide position 1505, causing the threonine (T) at amino acid position 502 to be replaced by an isoleucine (I). 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	0.087
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Benign	0.82
DEOGEN2	Benign	0.14	.;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.2	.;M
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.20
Sift	Benign	0.21	T;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.53	P;B
Vest4		0.33
MutPred		0.41		.;Loss of disorder (P = 0.0393);
MVP		0.58
MPC		0.16
ClinPred		0.25	T
GERP RS		3.2
Varity_R		0.059
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1406384562; hg19: chr4-54344890;