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 NM_001317073.1(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 NM_001317073.1 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001317073.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOX	NM_002317.7	MANE Select	c.893T>G	p.Met298Arg	missense	Exon 4 of 7	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	Exon 3 of 6	NP_001171573.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOX	ENST00000513319.5	TSL:1	c.2T>G	p.Met1?	start_lost	Exon 3 of 6	ENSP00000503104.1
	LOX	ENST00000231004.5	TSL:1 MANE Select	c.893T>G	p.Met298Arg	missense	Exon 4 of 7	ENSP00000231004.4
	LOX	ENST00000939087.1		c.893T>G	p.Met298Arg	missense	Exon 5 of 8	ENSP00000609146.1

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

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Aortic aneurysm, familial thoracic 10 (3)
1	-	-	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Pathogenic	3.3	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
Vest4		0.95
MutPred		0.85		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;