rs146972503

Positions:

• chr2-74552556-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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. 14/21 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.36

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]

ACMG classification

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 GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXL3	NM_032603.5	c.79C>G	p.Pro27Ala	missense_variant	2/14	ENST00000264094.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXL3	ENST00000264094.8	c.79C>G	p.Pro27Ala	missense_variant	2/14	1	NM_032603.5	P1

Frequencies

GnomAD3 genomes AF: 0.00229 AC: 348 AN: 152238 Hom.: 0 Cov.: 33

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

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

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

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	DOK1: BS2; LOXL3: BP4, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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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

Other links and lift over

dbSNP: rs146972503; hg19: chr2-74779683;