rs41407546

Variant names:

• chr5-122077510-G-T
• rs41407546
• NM_002317.7:c.476C>A

Variant summary

Our verdict is Benign. The variant received -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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P159P) has been classified 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:9
• Conservation: PhyloP100: 0.568
• Publications: 18 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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 948 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002317.7. 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.476C>A	p.Pro159Gln	missense	Exon 1 of 7	NP_002308.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOX	ENST00000231004.5	TSL:1 MANE Select	c.476C>A	p.Pro159Gln	missense	Exon 1 of 7	ENSP00000231004.4	P28300
	LOX	ENST00000939087.1		c.476C>A	p.Pro159Gln	missense	Exon 2 of 8	ENSP00000609146.1
	LOX	ENST00000639739.2	TSL:5	n.476C>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000492324.2	A0A7P0SNB0

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

GnomAD2 exomes AF: 0.00566 AC: 1408 AN: 248674 AF XY: 0.00578

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 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

African (AFR) AF: 0.00164 AC: 55 AN: 33480

American (AMR) AF: 0.00396 AC: 177 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26128

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

South Asian (SAS) AF: 0.00108 AC: 93 AN: 86256

European-Finnish (FIN) AF: 0.00478 AC: 254 AN: 53100

Middle Eastern (MID) AF: 0.0120 AC: 69 AN: 5768

European-Non Finnish (NFE) AF: 0.0108 AC: 12004 AN: 1111964

Other (OTH) AF: 0.00830 AC: 501 AN: 60384

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

African (AFR) AF: 0.00192 AC: 80 AN: 41584

American (AMR) AF: 0.00496 AC: 76 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00508 AC: 54 AN: 10626

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0103 AC: 704 AN: 68024

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00814 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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	1	Aortic aneurysm, familial thoracic 10 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.57
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
Vest4		0.16
MVP		0.26
MPC		0.88
ClinPred		0.013	T
GERP RS		3.4
PromoterAI		0.0059	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.099
gMVP		0.51
Mutation Taster		=98/2	polymorphism

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: rs41407546; hg19: chr5-121413205;