5-97105248-A-G

Variant names:

• chr5-97105248-A-G
• rs925733940
• NM_153234.5:c.425T>C

Variant summary

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

The NM_153234.5(LIX1):​c.425T>C​(p.Val142Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,788 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V142D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LIX1 NM_153234.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.90
• Publications: 0 publications found

Genes affected

LIX1 (HGNC:18581): (limb and CNS expressed 1) Predicted to be involved in autophagosome maturation. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

LIX1-AS1 (HGNC:52976): (LIX1 and RIOK2 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIX1	NM_153234.5	c.425T>C	p.Val142Ala	missense_variant	Exon 4 of 6	ENST00000274382.9	NP_694966.3
LIX1-AS1	NR_187470.1	n.824+2154A>G		intron_variant	Intron 7 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIX1	ENST00000274382.9	c.425T>C	p.Val142Ala	missense_variant	Exon 4 of 6	1	NM_153234.5	ENSP00000274382.4
LIX1-AS1	ENST00000504578.2	n.573+2154A>G		intron_variant	Intron 3 of 6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461788 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727202

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111926

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.075
Eigen_PC	Benign	0.029
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N
PhyloP100		8.9
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.011	D
Polyphen		0.12	B
Vest4		0.63
MutPred		0.30		Gain of disorder (P = 0.0285);
MVP		0.42
MPC		0.25
ClinPred		0.57	D
GERP RS		5.8
Varity_R		0.31
gMVP		0.49
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs925733940; hg19: chr5-96440952;