rs41407546

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002317.7(LOX):c.476C>A(p.Pro159Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00876 in 1,613,824 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P159P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0062 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0090 ( 69 hom. )

Consequence

LOX
NM_002317.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.568

Publications

18 publications found

Variant links:

Genes affected

LOX (HGNC:6664): (lysyl oxidase) This gene encodes a member of the lysyl oxidase family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate a regulatory propeptide and the mature enzyme. The copper-dependent amine oxidase activity of this enzyme functions in the crosslinking of collagens and elastin, while the propeptide may play a role in tumor suppression. In addition, defects in this gene have been linked with predisposition to thoracic aortic aneurysms and dissections. [provided by RefSeq, Jul 2016]

LOX links:

SRFBP1 (HGNC:26333): (serum response factor binding protein 1) Enables RNA binding activity. Predicted to be involved in maturation of SSU-rRNA. Predicted to be located in perinuclear region of cytoplasm. Predicted to be part of 90S preribosome. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SRFBP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0066544116).

BP6

Variant 5-122077510-G-T is Benign according to our data. Variant chr5-122077510-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00622 (948/152324) while in subpopulation NFE AF = 0.0103 (704/68024). AF 95% confidence interval is 0.00972. There are 4 homozygotes in GnomAd4. There are 415 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 948 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOX	NM_002317.7 link	c.476C>A	p.Pro159Gln	missense_variant	Exon 1 of 7	ENST00000231004.5	NP_002308.2	P28300D0PNI2
SRFBP1	XM_017009111.3 link	c.*2185G>T		3_prime_UTR_variant	Exon 8 of 8		XP_016864600.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LOX	ENST00000231004.5 link	c.476C>A	p.Pro159Gln	missense_variant	Exon 1 of 7	1	NM_002317.7	ENSP00000231004.4	P28300
LOX	ENST00000639739.2 link	n.476C>A		non_coding_transcript_exon_variant	Exon 1 of 6	5		ENSP00000492324.2	A0A7P0SNB0
LOX	ENST00000508067.1 link	n.-38C>A		upstream_gene_variant		4		ENSP00000427538.1	H0YAL3

Frequencies

GnomAD3 genomes

AF:

0.00623

AC:

948

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00193

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00497

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00508

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0103

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00566

AC:

1408

AN:

248674

AF XY:

0.00578

show subpopulations

Gnomad AFR exome

AF:

0.00162

Gnomad AMR exome

AF:

0.00382

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00542

Gnomad NFE exome

AF:

0.00932

Gnomad OTH exome

AF:

0.00707

GnomAD4 exome

AF:

0.00903

AC:

13194

AN:

1461500

Hom.:

Cov.:

AF XY:

0.00883

AC XY:

6423

AN XY:

727070

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

33480

American (AMR)

AF:

0.00396

AC:

177

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00157

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00108

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00478

AC:

254

AN:

53100

Middle Eastern (MID)

AF:

0.0120

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0108

AC:

12004

AN:

1111964

Other (OTH)

AF:

0.00830

AC:

501

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

837

1675

2512

3350

4187

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

464

928

1392

1856

2320

<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

AF:

0.00622

AC:

948

AN:

152324

Hom.:

Cov.:

AF XY:

0.00557

AC XY:

415

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00192

AC:

AN:

41584

American (AMR)

AF:

0.00496

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00508

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0103

AC:

704

AN:

68024

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

148

198

247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00814

Hom.:

Bravo

AF:

0.00580

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00931

AC:

ExAC

AF:

0.00546

AC:

662

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0110

EpiControl

AF:

0.0113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LOX: BP4, BS1, BS2 -

Aug 10, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 14, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The LOX c.476C>A (p.Pro159Gln) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index), however in silico prediction results are not definitive. This variant was found in 659/118824 control chromosomes (4 homozygotes) from ExAC at a frequency of 0.005546, which is approximately 333 times the estimated maximal expected allele frequency of a pathogenic LOX variant (0.0000167), suggesting this variant is likely a benign polymorphism. It has been reported as a polymorphism in literature (De Bonis_2011). Taken together, this variant is classified as benign. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1;BP4;BP6 -

Aortic aneurysm, familial thoracic 10

Benign:1

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jan 18, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.36

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.55

.;T

M_CAP

Benign

0.0098

MetaRNN

Benign

0.0067

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L

PhyloP100

0.57

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.0

N;.

REVEL

Benign

0.088

Sift

Uncertain

0.0080

D;.

Sift4G

Uncertain

0.051

T;.

Polyphen

0.41

B;B

Vest4

0.16

MVP

0.26

MPC

0.88

ClinPred

0.013

GERP RS

3.4

PromoterAI

0.0059

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.099

gMVP

0.51

Mutation Taster

=98/2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over