rs41407546

Positions:

• chr5-122077510-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0090 (69 hom.)
• Consequence: LOX NM_002317.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.568

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=0.0066544116).
• BP6: Variant 5-122077510-G-T is Benign according to our data. Variant chr5-122077510-G-T is described in ClinVar as [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 948 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOX	NM_002317.7	c.476C>A	p.Pro159Gln	missense_variant	1/7	ENST00000231004.5	NP_002308.2
SRFBP1	XM_017009111.3	c.*2185G>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.476C>A	p.Pro159Gln	missense_variant	1/7	1	NM_002317.7	ENSP00000231004.4
LOX	ENST00000639739.2	n.476C>A		non_coding_transcript_exon_variant	1/6	5		ENSP00000492324.2
LOX	ENST00000508067.1	n.-38C>A		upstream_gene_variant		4		ENSP00000427538.1

Frequencies

GnomAD3 genomes AF: 0.00623 AC: 948 AN: 152206 Hom.: 4 Cov.: 32

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

GnomAD3 exomes AF: 0.00566 AC: 1408 AN: 248674 Hom.: 12 AF XY: 0.00578 AC XY: 782 AN XY: 135220

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 SAS exome AF: 0.000947

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.: 69 Cov.: 33 AF XY: 0.00883 AC XY: 6423 AN XY: 727070

Gnomad4 AFR exome AF: 0.00164

Gnomad4 AMR exome AF: 0.00396

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00108

Gnomad4 FIN exome AF: 0.00478

Gnomad4 NFE exome AF: 0.0108

Gnomad4 OTH exome AF: 0.00830

GnomAD4 genome AF: 0.00622 AC: 948 AN: 152324 Hom.: 4 Cov.: 32 AF XY: 0.00557 AC XY: 415 AN XY: 74490

Gnomad4 AFR AF: 0.00192

Gnomad4 AMR AF: 0.00496

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00508

Gnomad4 NFE AF: 0.0103

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00868 Hom.: 15

Bravo AF: 0.00580

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00931 AC: 80

ExAC AF: 0.00546 AC: 662

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0110

EpiControl AF: 0.0113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 14, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 10, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	LOX: BP4, BS1, BS2 -

Aortic aneurysm, familial thoracic 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 02, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2019

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	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.86
DEOGEN2	Benign	0.36	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.55	.;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.0067	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Benign	0.45	T
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	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.099
gMVP		0.51

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: rs41407546; hg19: chr5-121413205;