rs886040965

Variant names:

• chr5-122075443-C-A
• rs886040965
• NM_002317.7:c.839G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_002317.7(LOX):​c.839G>T​(p.Ser280Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S280R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LOX NM_002317.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 2.99
• Publications: 5 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-122075443-C-A is Pathogenic according to our data. Variant chr5-122075443-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 267291.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3049927). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOX	NM_002317.7	c.839G>T	p.Ser280Ile	missense_variant	Exon 3 of 7	ENST00000231004.5	NP_002308.2
LOX	NM_001178102.2	c.149G>T	p.Ser50Ile	missense_variant	Exon 2 of 6		NP_001171573.1
LOX	NM_001317073.1	c.-53G>T		5_prime_UTR_variant	Exon 2 of 6		NP_001304002.1
SRFBP1	XM_017009111.3	c.*118C>A		3_prime_UTR_variant	Exon 8 of 8		XP_016864600.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LOX	ENST00000231004.5	c.839G>T	p.Ser280Ile	missense_variant	Exon 3 of 7	1	NM_002317.7	ENSP00000231004.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Aortic aneurysm, familial thoracic 10 Pathogenic:1

Oct 24, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Acute aortic dissection;C0345050:Congenital aneurysm of ascending aorta Pathogenic:1

Jan 12, 2016

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.84	.;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;M
PhyloP100		3.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.3	D;.
REVEL	Benign	0.054
Sift	Benign	0.067	T;.
Sift4G	Benign	0.21	T;.
Polyphen		0.42	B;B
Vest4		0.62
MutPred		0.37		Loss of disorder (P = 0.0045);Loss of disorder (P = 0.0045);
MVP		0.20
MPC		1.3
ClinPred		0.96	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.73
Mutation Taster		=18/82	disease causing (ClinVar)

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: rs886040965; hg19: chr5-121411138;