dbSNP rs1048661: LOXL1:p.Arg141Gln (chr15-73927205-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NR_040069.1(LOXL1-AS1):n.184+860C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,439,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

LOXL1-AS1
NR_040069.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.83

Publications

171 publications found

Variant links:

Genes affected

LOXL1 (HGNC:6665): (lysyl oxidase like 1) This gene encodes a member of the lysyl oxidase family of proteins. The prototypic member of the family is essential to the biogenesis of connective tissue, encoding an extracellular copper-dependent amine oxidase that catalyzes the first step in the formation of crosslinks in collagen and elastin. The encoded preproprotein is proteolytically processed to generate the mature enzyme. A highly conserved amino acid sequence at the C-terminus end appears to be sufficient for amine oxidase activity, suggesting that each family member may retain this function. The N-terminus is poorly conserved and may impart additional roles in developmental regulation, senescence, tumor suppression, cell growth control, and chemotaxis to each member of the family. Mutations in this gene are associated with exfoliation syndrome. [provided by RefSeq, Jan 2016]

LOXL1 links:

LOXL1-AS1 (HGNC:44169): (LOXL1 antisense RNA 1)

LOXL1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15081781).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NR_040069.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LOXL1	NM_005576.4	MANE Select	c.422G>A	p.Arg141Gln	missense	Exon 1 of 7	NP_005567.2	Q08397
LOXL1-AS1	NR_040066.1		n.133+449C>T		intron	N/A
LOXL1-AS1	NR_040067.1		n.133+449C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LOXL1	ENST00000261921.8	TSL:1 MANE Select	c.422G>A	p.Arg141Gln	missense	Exon 1 of 7	ENSP00000261921.7	Q08397
LOXL1	ENST00000856631.1		c.422G>A	p.Arg141Gln	missense	Exon 1 of 6	ENSP00000526690.1
LOXL1	ENST00000566011.5	TSL:5	n.422G>A		non_coding_transcript_exon	Exon 1 of 8	ENSP00000457827.1	H3BUV8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.95e-7

AC:

AN:

1439534

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716566

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

31680

American (AMR)

AF:

0.00

AC:

AN:

43652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25698

East Asian (EAS)

AF:

0.00

AC:

AN:

38492

South Asian (SAS)

AF:

0.00

AC:

AN:

84678

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43276

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106604

Other (OTH)

AF:

0.00

AC:

AN:

59772

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

3624

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.62

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.093

Eigen

Benign

-0.052

Eigen_PC

Benign

0.061

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.79

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.97

PhyloP100

1.8

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.59

REVEL

Benign

0.056

Sift

Benign

0.073

Sift4G

Benign

0.50

Polyphen

0.28

Vest4

0.028

MutPred

0.21

Loss of methylation at R141 (P = 0.0102)

MVP

0.39

ClinPred

0.61

GERP RS

4.1

Varity_R

0.22

gMVP

0.29

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over