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rs146972503

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_032603.5(LOXL3):c.79C>G(p.Pro27Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,611,874 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. P27P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0023 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0027 ( 14 hom. )

Consequence

LOXL3
NM_032603.5 missense

Scores

2
17

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.36
Variant links:
Genes affected
LOXL3 (HGNC:13869): (lysyl oxidase like 3) This gene encodes a lysyl oxidase, which likely functions as an amine oxidase and plays a role in the formation of crosslinks in collagens and elastin. Deletion of the related gene in mouse causes neonatal mortality with cleft palate, spine deformity, and defects in collagen organization. A mutation in this gene was found in a family with Stickler syndrome. [provided by RefSeq, Sep 2016]
DOK1 (HGNC:2990): (docking protein 1) The protein encoded by this gene is part of a signal transduction pathway downstream of receptor tyrosine kinases. The encoded protein is a scaffold protein that helps form a platform for the assembly of multiprotein signaling complexes. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0051018).
BP6
Variant 2-74552556-G-C is Benign according to our data. Variant chr2-74552556-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 262092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74552556-G-C is described in Lovd as [Likely_benign].
BS2
High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LOXL3NM_032603.5 linkuse as main transcriptc.79C>G p.Pro27Ala missense_variant 2/14 ENST00000264094.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LOXL3ENST00000264094.8 linkuse as main transcriptc.79C>G p.Pro27Ala missense_variant 2/141 NM_032603.5 P1P58215-1

Frequencies

GnomAD3 genomes
AF:
0.00229
AC:
348
AN:
152238
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000651
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000916
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00207
Gnomad FIN
AF:
0.00395
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.00369
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.00214
AC:
520
AN:
242750
Hom.:
5
AF XY:
0.00228
AC XY:
303
AN XY:
132778
show subpopulations
Gnomad AFR exome
AF:
0.000470
Gnomad AMR exome
AF:
0.000819
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000990
Gnomad FIN exome
AF:
0.00409
Gnomad NFE exome
AF:
0.00335
Gnomad OTH exome
AF:
0.000845
GnomAD4 exome
AF:
0.00274
AC:
3992
AN:
1459518
Hom.:
14
Cov.:
31
AF XY:
0.00273
AC XY:
1985
AN XY:
725904
show subpopulations
Gnomad4 AFR exome
AF:
0.000628
Gnomad4 AMR exome
AF:
0.000898
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00107
Gnomad4 FIN exome
AF:
0.00345
Gnomad4 NFE exome
AF:
0.00315
Gnomad4 OTH exome
AF:
0.00234
GnomAD4 genome
AF:
0.00228
AC:
347
AN:
152356
Hom.:
0
Cov.:
33
AF XY:
0.00230
AC XY:
171
AN XY:
74494
show subpopulations
Gnomad4 AFR
AF:
0.000649
Gnomad4 AMR
AF:
0.000914
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00207
Gnomad4 FIN
AF:
0.00395
Gnomad4 NFE
AF:
0.00367
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.00325
Hom.:
2
Bravo
AF:
0.00189
TwinsUK
AF:
0.00351
AC:
13
ALSPAC
AF:
0.00234
AC:
9
ESP6500AA
AF:
0.000682
AC:
3
ESP6500EA
AF:
0.00326
AC:
28
ExAC
AF:
0.00184
AC:
223
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 29, 2024- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2023DOK1: BS2; LOXL3: BP4, BS2 -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.057
BayesDel_addAF
Benign
-0.48
T
BayesDel_noAF
Benign
-0.46
Cadd
Benign
22
Dann
Uncertain
1.0
DEOGEN2
Benign
0.043
T;T;.;T;.;.
Eigen
Benign
-0.063
Eigen_PC
Benign
0.11
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.81
T;T;T;T;T;T
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.0051
T;T;T;T;T;T
MetaSVM
Benign
-0.68
T
MutationAssessor
Benign
0.81
L;.;L;.;.;.
MutationTaster
Benign
0.68
N;N;N;N;N;D
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-1.6
N;N;N;N;N;N
REVEL
Benign
0.067
Sift
Benign
0.21
T;T;T;T;T;D
Sift4G
Benign
0.20
T;T;T;T;T;.
Polyphen
0.13
B;.;.;B;B;.
Vest4
0.25
MVP
0.42
MPC
1.2
ClinPred
0.011
T
GERP RS
4.8
Varity_R
0.098
gMVP
0.56

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs146972503; hg19: chr2-74779683; API