5-122077513-C-T

Position:

• chr5-122077513-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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

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

Verdict is Benign. Variant got -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 id is 14363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-122077513-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOX	NM_002317.7	c.473G>A	p.Arg158Gln	missense_variant	1/7	ENST00000231004.5	NP_002308.2
SRFBP1	XM_017009111.3	c.*2188C>T		3_prime_UTR_variant	8/8		XP_016864600.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LOX	ENST00000231004.5	c.473G>A	p.Arg158Gln	missense_variant	1/7	1	NM_002317.7	ENSP00000231004.4
LOX	ENST00000639739.2	n.473G>A		non_coding_transcript_exon_variant	1/6	5		ENSP00000492324.2
LOX	ENST00000508067.1	n.-41G>A		upstream_gene_variant		4		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

GnomAD3 exomes AF: 0.172 AC: 42767 AN: 248724 Hom.: 3752 AF XY: 0.172 AC XY: 23253 AN XY: 135190

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 SAS exome AF: 0.172

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

Gnomad4 AFR exome AF: 0.170

Gnomad4 AMR exome AF: 0.182

Gnomad4 ASJ exome AF: 0.163

Gnomad4 EAS exome AF: 0.189

Gnomad4 SAS exome AF: 0.171

Gnomad4 FIN exome AF: 0.146

Gnomad4 NFE exome AF: 0.170

Gnomad4 OTH exome AF: 0.173

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

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.184

Gnomad4 ASJ AF: 0.166

Gnomad4 EAS AF: 0.191

Gnomad4 SAS AF: 0.159

Gnomad4 FIN AF: 0.138

Gnomad4 NFE AF: 0.171

Gnomad4 OTH AF: 0.182

Alfa AF: 0.167 Hom.: 4593

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2018	This variant is associated with the following publications: (PMID: 28714974, 24502826, 22661479, 19654310, 20929399, 22911823) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 04, 2023

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

Benign, criteria provided, single submitter

clinical testing

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

Nov 18, 2022

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2018

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

Benign, no assertion criteria provided

literature only

OMIM

May 01, 1993

- -

Computational scores

Source: dbNSFP v4.3

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;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;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.97	L;L
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;B
Vest4		0.018
MPC		0.62
ClinPred		0.0029	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.38

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

Other links and lift over

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