rs886040967

chr5-122075482-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_002317.7(LOX):c.800A>C(p.Gln267Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LOX NM_002317.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 5.95

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a chain Protein-lysine 6-oxidase, short form (size 198) in uniprot entity LYOX_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_002317.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88
• PP5: Variant 5-122075482-T-G is Pathogenic according to our data. Variant chr5-122075482-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 267293.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOX	NM_002317.7	c.800A>C	p.Gln267Pro	missense_variant	3/7	ENST00000231004.5
LOX	NM_001178102.2	c.110A>C	p.Gln37Pro	missense_variant	2/6
LOX	NM_001317073.1	c.-92A>C		5_prime_UTR_variant	2/6
SRFBP1	XM_017009111.3	c.*157T>G		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOX	ENST00000231004.5	c.800A>C	p.Gln267Pro	missense_variant	3/7	1	NM_002317.7	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 24, 2016

- -

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

Pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

Jan 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.9	D;.
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0070	D;.
Sift4G	Uncertain	0.0080	D;.
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.62		Gain of catalytic residue at P266 (P = 0.0133);Gain of catalytic residue at P266 (P = 0.0133);
MVP		0.81
MPC		1.6
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.91
gMVP		0.94

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: rs886040967; hg19: chr5-121411177;