chr5-122074155-A-C

Variant names:

• chr5-122074155-A-C
• rs876657852
• ENST00000513319.5:c.2T>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000513319.5(LOX):​c.2T>G​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LOX ENST00000513319.5 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.95
• Publications: 11 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-122074155-A-C is Pathogenic according to our data. Variant chr5-122074155-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 228806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOX	NM_002317.7	c.893T>G	p.Met298Arg	missense_variant	Exon 4 of 7	ENST00000231004.5	NP_002308.2
LOX	NM_001317073.1	c.2T>G	p.Met1?	start_lost	Exon 3 of 6		NP_001304002.1
LOX	NM_001178102.2	c.203T>G	p.Met68Arg	missense_variant	Exon 3 of 6		NP_001171573.1
SRFBP1	XM_017009111.3	c.1106-1160A>C		intron_variant	Intron 7 of 7		XP_016864600.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LOX	ENST00000231004.5	c.893T>G	p.Met298Arg	missense_variant	Exon 4 of 7	1	NM_002317.7	ENSP00000231004.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461736 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727148

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111894

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aortic aneurysm, familial thoracic 10 Pathogenic:3

Feb 19, 2021

Centre of Medical Genetics, University of Antwerp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PP3, PM1, PM2, PS1, PS3 -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 24, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Jan 25, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Met298Arg variant in LOX has been reported in 1 individual with thoracic aortic aneurysms and dissections (TAAD) and segregated with TAAD in 3 affected relatives. Additionally, one older relative (76 y.o.) had arterial tortuosity which could be explained by aging (Lee 2016 PMID: 27432961). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 228806) and was absent from large population studies. A mouse model provides some evidence that this variant causes TAAD (Lee 2016 PMID: 27432961). Furthermore, this variant is located in the LOX catalytic domain, which is relatively invariant in the general population and is where all disease-causing missense variants have been located to date (Guo 2016 PMID: 26838787). Computational prediction tools and conservation analysis are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PP1, PM2_Supporting, PS3_Moderate, PM1, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Pathogenic	3.3	M;M
PhyloP100		8.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.0	D;.
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;D
Vest4		0.95
MutPred		0.85		Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);
MVP		0.77
MPC		1.7
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.96
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs876657852; hg19: chr5-121409850;