rs752839330

Positions:

chr5-122077751-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_002317.7(LOX):c.235G>A(p.Ala79Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000425 in 1,562,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A79A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00045 ( 0 hom. )

Consequence

LOX
NM_002317.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 0.319

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:):

SRFBP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.036512703).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000151 (23/152130) while in subpopulation NFE AF= 0.000294 (20/68012). AF 95% confidence interval is 0.000194. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOX	NM_002317.7 linkuse as main transcript	c.235G>A	p.Ala79Thr	missense_variant	1/7	ENST00000231004.5
SRFBP1	XM_017009111.3 linkuse as main transcript	c.*2426C>T		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOX	ENST00000231004.5 linkuse as main transcript	c.235G>A	p.Ala79Thr	missense_variant	1/7	1	NM_002317.7	P1
LOX	ENST00000639739.2 linkuse as main transcript	c.235G>A	p.Ala79Thr	missense_variant, NMD_transcript_variant	1/6	5

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000164

AC:

AN:

158608

Hom.:

AF XY:

0.000148

AC XY:

AN XY:

87574

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000401

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000455

AC:

641

AN:

1410310

Hom.:

Cov.:

AF XY:

0.000402

AC XY:

281

AN XY:

698184

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000244

Gnomad4 NFE exome

AF:

0.000573

Gnomad4 OTH exome

AF:

0.000256

GnomAD4 genome

AF:

0.000151

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000117

Hom.:

Bravo

AF:

0.000155

ExAC

AF:

0.000215

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 79 of the LOX protein (p.Ala79Thr). This variant is present in population databases (rs752839330, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with thoracic aortic aneurysms and dissections (PMID: 26838787). ClinVar contains an entry for this variant (Variation ID: 521345). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LOX protein function with a negative predictive value of 80%. 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	Jan 26, 2023	Identified in two families with TAA, one of whom harbored an additional disease-causing variant in the ACTA2 gene; authors report p.(A79T) as likely benign (Guo et. al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26838787) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 01, 2024

Variant summary: LOX c.235G>A (p.Ala79Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 158608 control chromosomes. The observed variant frequency is approximately 99-fold of the estimated maximal expected allele frequency for a pathogenic variant in LOX causing Aortopathy phenotype (1.7e-06), suggesting that the variant could be benign. c.235G>A has been reported in the literature in at least one individual affected with familial thoracic aortic aneurysms and dissections with a reported alternate disease-causing ACTA2 mutation (e.g. Guo_2017). This report does not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 521345). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Acute aortic dissection;C0345050:Congenital aneurysm of ascending aorta

Benign:1

Benign, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

Jan 12, 2016

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2023

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

0.072

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.72

CADD

Benign

3.0

DANN

Benign

0.87

DEOGEN2

Benign

0.22

T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.46

.;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.037

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.93

N;.

REVEL

Benign

0.024

Sift

Benign

0.076

T;.

Sift4G

Benign

0.71

T;.

Polyphen

0.0

B;B

Vest4

0.10

MVP

0.15

MPC

0.52

ClinPred

0.027

GERP RS

-0.81

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.046

gMVP

0.36

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

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