5-122070053-G-A

Position:

chr5-122070053-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP3BS2

The NM_002317.7(LOX):c.1247C>T(p.Pro416Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000231 in 1,598,502 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

LOX
NM_002317.7 missense, splice_region

Scores

Splicing: ADA: 0.9880

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.89

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 made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a region_of_interest Lysyl-oxidase like (size 204) in uniprot entity LYOX_HUMAN there are 8 pathogenic changes around while only 3 benign (73%) in NM_002317.7

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BS2

High AC in GnomAdExome4 at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LOX	NM_002317.7 linkuse as main transcript	c.1247C>T	p.Pro416Leu	missense_variant, splice_region_variant	6/7	ENST00000231004.5
LOX	NM_001178102.2 linkuse as main transcript	c.557C>T	p.Pro186Leu	missense_variant, splice_region_variant	5/6
LOX	NM_001317073.1 linkuse as main transcript	c.356C>T	p.Pro119Leu	missense_variant, splice_region_variant	5/6
SRFBP1	XM_017009111.3 linkuse as main transcript	c.1106-5262G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOX	ENST00000231004.5 linkuse as main transcript	c.1247C>T	p.Pro416Leu	missense_variant, splice_region_variant	6/7	1	NM_002317.7	P1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251060

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135676

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000249

AC:

AN:

1446494

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

720536

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000673

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000466

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000228

Gnomad4 OTH exome

AF:

0.0000335

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152008

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 416 of the LOX protein (p.Pro416Leu). This variant is present in population databases (rs770316240, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with LOX-related conditions. ClinVar contains an entry for this variant (Variation ID: 1313512). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2020	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

D;D

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

.;T

M_CAP

Benign

0.044

MetaRNN

Uncertain

0.51

D;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.4

D;.

REVEL

Benign

0.14

Sift

Uncertain

0.0030

D;.

Sift4G

Uncertain

0.035

D;.

Polyphen

0.99

D;D

Vest4

0.65

MutPred

0.53

Loss of glycosylation at T413 (P = 0.0452);Loss of glycosylation at T413 (P = 0.0452);

MVP

0.24

MPC

1.4

ClinPred

0.81

GERP RS

5.3

Varity_R

0.26

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.80

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over