rs77706750

Positions:

• chr2-74536120-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032603.5(LOXL3):​c.1124G>A​(p.Arg375His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,613,852 control chromosomes in the GnomAD database, including 373 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R375C) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.015 (24 hom., cov: 32)
  • Exomes 𝑓: 0.019 (349 hom.)
• Consequence: LOXL3 NM_032603.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.937

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014687121).
• BP6: Variant 2-74536120-C-T is Benign according to our data. Variant chr2-74536120-C-T is described in ClinVar as [Benign]. Clinvar id is 262090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74536120-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0146 (2221/152238) while in subpopulation NFE AF= 0.0232 (1577/67998). AF 95% confidence interval is 0.0222. There are 24 homozygotes in gnomad4. There are 1026 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOXL3	NM_032603.5	c.1124G>A	p.Arg375His	missense_variant	7/14	ENST00000264094.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LOXL3	ENST00000264094.8	c.1124G>A	p.Arg375His	missense_variant	7/14	1	NM_032603.5	P1

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2224 AN: 152120 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00512

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0232

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.0147 AC: 3687 AN: 251176 Hom.: 40 AF XY: 0.0153 AC XY: 2079 AN XY: 135772

Gnomad AFR exome AF: 0.00449

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.00864

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00510

Gnomad FIN exome AF: 0.0123

Gnomad NFE exome AF: 0.0228

Gnomad OTH exome AF: 0.0171

GnomAD4 exome AF: 0.0194 AC: 28340 AN: 1461614 Hom.: 349 Cov.: 32 AF XY: 0.0192 AC XY: 13969 AN XY: 727128

Gnomad4 AFR exome AF: 0.00343

Gnomad4 AMR exome AF: 0.0115

Gnomad4 ASJ exome AF: 0.00731

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00541

Gnomad4 FIN exome AF: 0.0129

Gnomad4 NFE exome AF: 0.0228

Gnomad4 OTH exome AF: 0.0162

GnomAD4 genome AF: 0.0146 AC: 2221 AN: 152238 Hom.: 24 Cov.: 32 AF XY: 0.0138 AC XY: 1026 AN XY: 74416

Gnomad4 AFR AF: 0.00510

Gnomad4 AMR AF: 0.0139

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00353

Gnomad4 FIN AF: 0.0119

Gnomad4 NFE AF: 0.0232

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0201 Hom.: 62

Bravo AF: 0.0141

TwinsUK AF: 0.0232 AC: 86

ALSPAC AF: 0.0262 AC: 101

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.0231 AC: 199

ExAC AF: 0.0149 AC: 1803

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0219

EpiControl AF: 0.0252

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	T;.;T;.
Eigen	Benign	0.079
Eigen_PC	Benign	0.094
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.85	T;T;D;T
MetaRNN	Benign	0.015	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.98	L;.;.;.
MutationTaster	Benign	0.91	D;D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Benign	0.068
Sift	Benign	0.067	T;T;D;T
Sift4G	Benign	0.47	T;T;D;T
Polyphen		0.96	D;.;P;D
Vest4		0.082
MPC		1.0
ClinPred		0.014	T
GERP RS		4.2
Varity_R		0.052
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs77706750; hg19: chr2-74763247;