5-122077513-C-T

Variant names:

• chr5-122077513-C-T
• rs1800449
• NM_002317.7:c.473G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002317.7(LOX):​c.473G>A​(p.Arg158Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,613,690 control chromosomes in the GnomAD database, including 23,736 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R158L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.17 (2280 hom., cov: 33)
  • Exomes 𝑓: 0.17 (21456 hom.)
• Consequence: LOX NM_002317.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0900
• Publications: 117 publications found

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]

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011650324).
• BP6: Variant 5-122077513-C-T is Benign according to our data. Variant chr5-122077513-C-T is described in ClinVar as Benign. ClinVar VariationId is 14363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002317.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOX	NM_002317.7	MANE Select	c.473G>A	p.Arg158Gln	missense	Exon 1 of 7	NP_002308.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOX	ENST00000231004.5	TSL:1 MANE Select	c.473G>A	p.Arg158Gln	missense	Exon 1 of 7	ENSP00000231004.4
	LOX	ENST00000639739.2	TSL:5	n.473G>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000492324.2
	LOX	ENST00000508067.1	TSL:4	n.-41G>A		upstream_gene	N/A	ENSP00000427538.1

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25752 AN: 152054 Hom.: 2278 Cov.: 33

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.138

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.183

GnomAD2 exomes AF: 0.172 AC: 42767 AN: 248724 AF XY: 0.172

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.162

Gnomad EAS exome AF: 0.204

Gnomad FIN exome AF: 0.142

Gnomad NFE exome AF: 0.171

Gnomad OTH exome AF: 0.171

GnomAD4 exome AF: 0.170 AC: 248906 AN: 1461518 Hom.: 21456 Cov.: 34 AF XY: 0.170 AC XY: 123922 AN XY: 727082

African (AFR) AF: 0.170 AC: 5682 AN: 33480

American (AMR) AF: 0.182 AC: 8142 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 4249 AN: 26128

East Asian (EAS) AF: 0.189 AC: 7508 AN: 39698

South Asian (SAS) AF: 0.171 AC: 14726 AN: 86258

European-Finnish (FIN) AF: 0.146 AC: 7772 AN: 53110

Middle Eastern (MID) AF: 0.178 AC: 1029 AN: 5768

European-Non Finnish (NFE) AF: 0.170 AC: 189376 AN: 1111966

Other (OTH) AF: 0.173 AC: 10422 AN: 60388

GnomAD4 genome AF: 0.169 AC: 25765 AN: 152172 Hom.: 2280 Cov.: 33 AF XY: 0.166 AC XY: 12327 AN XY: 74386

African (AFR) AF: 0.170 AC: 7061 AN: 41534

American (AMR) AF: 0.184 AC: 2815 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 576 AN: 3470

East Asian (EAS) AF: 0.191 AC: 980 AN: 5142

South Asian (SAS) AF: 0.159 AC: 767 AN: 4822

European-Finnish (FIN) AF: 0.138 AC: 1465 AN: 10600

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11635 AN: 67992

Other (OTH) AF: 0.182 AC: 384 AN: 2108

Alfa AF: 0.169 Hom.: 9155

Bravo AF: 0.177

TwinsUK AF: 0.159 AC: 590

ALSPAC AF: 0.166 AC: 638

ESP6500AA AF: 0.178 AC: 784

ESP6500EA AF: 0.174 AC: 1494

ExAC AF: 0.170 AC: 20681

Asia WGS AF: 0.144 AC: 500 AN: 3478

EpiCase AF: 0.168

EpiControl AF: 0.172

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Sep 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28714974, 24502826, 22661479, 19654310, 20929399, 22911823)

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 04, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LOX c.473G>A (p.Arg158Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.17 in 248724 control chromosomes in the gnomAD database, including 3752 homozygotes. The observed variant frequency exceeds the estimated maximal expected allele frequency for a pathogenic variant in LOX causing Aortopathy phenotype (1.7e-06), strongly suggesting that the variant is benign. To our knowledge, no penetrant association or occurrence of c.473G>A in individuals affected with Aortopathy has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Nov 18, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

Dec 04, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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.

LOX POLYMORPHISM Benign:1

May 01, 1993

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	8.5
DANN	Benign	0.95
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.97	L
PhyloP100		-0.090
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.68	N
REVEL	Benign	0.048
Sift	Benign	0.54	T
Sift4G	Benign	0.75	T
Polyphen		0.0	B
Vest4		0.018
MPC		0.62
ClinPred		0.0029	T
GERP RS		2.4
PromoterAI		-0.0086	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.38
Mutation Taster		=97/3	polymorphism (auto)

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: rs1800449; hg19: chr5-121413208; COSMIC: COSV50237378; COSMIC: COSV50237378;