rs17010022

Variant names:

• chr2-74536131-C-G
• rs17010022
• NM_032603.5:c.1113G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-74536131-C-G
• chr2-74536131-C-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_Strong BP7 BA1

The NM_032603.5(LOXL3):​c.1113G>C​(p.Leu371Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 1,613,850 control chromosomes in the GnomAD database, including 2,773 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (393 hom., cov: 32)
  • Exomes 𝑓: 0.015 (2380 hom.)
• Consequence: LOXL3 NM_032603.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.28
• Publications: 8 publications found

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]

LOXL3 Gene-Disease associations (from GenCC):

• myopia 28, autosomal recessive

  Inheritance: AR, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Stickler syndrome

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp
• autosomal recessive Stickler syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP6: Variant 2-74536131-C-G is Benign according to our data. Variant chr2-74536131-C-G is described in ClinVar as Benign. ClinVar VariationId is 1239926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032603.5. 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
	LOXL3	NM_032603.5	MANE Select	c.1113G>C	p.Leu371Leu	synonymous	Exon 7 of 14	NP_115992.1
	LOXL3	NM_001289164.3		c.678G>C	p.Leu226Leu	synonymous	Exon 5 of 12	NP_001276093.1
	LOXL3	NM_001289165.2		c.30G>C	p.Leu10Leu	synonymous	Exon 3 of 10	NP_001276094.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXL3	ENST00000264094.8	TSL:1 MANE Select	c.1113G>C	p.Leu371Leu	synonymous	Exon 7 of 14	ENSP00000264094.3
	LOXL3	ENST00000946469.1		c.1113G>C	p.Leu371Leu	synonymous	Exon 6 of 13	ENSP00000616528.1
	LOXL3	ENST00000853956.1		c.1113G>C	p.Leu371Leu	synonymous	Exon 7 of 14	ENSP00000524015.1

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3457 AN: 152168 Hom.: 389 Cov.: 32

Gnomad AFR AF: 0.00533

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0812

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.322

Gnomad SAS AF: 0.0348

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.0253

GnomAD2 exomes AF: 0.0495 AC: 12431 AN: 251136 AF XY: 0.0429

Gnomad AFR exome AF: 0.00474

Gnomad AMR exome AF: 0.145

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.339

Gnomad FIN exome AF: 0.000280

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.0308

GnomAD4 exome AF: 0.0148 AC: 21689 AN: 1461564 Hom.: 2380 Cov.: 33 AF XY: 0.0142 AC XY: 10322 AN XY: 727116

African (AFR) AF: 0.00260 AC: 87 AN: 33480

American (AMR) AF: 0.141 AC: 6294 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00264 AC: 69 AN: 26132

East Asian (EAS) AF: 0.269 AC: 10664 AN: 39700

South Asian (SAS) AF: 0.0235 AC: 2023 AN: 86254

European-Finnish (FIN) AF: 0.000282 AC: 15 AN: 53124

Middle Eastern (MID) AF: 0.00572 AC: 33 AN: 5768

European-Non Finnish (NFE) AF: 0.000723 AC: 804 AN: 1112000

Other (OTH) AF: 0.0282 AC: 1700 AN: 60390

GnomAD4 genome AF: 0.0227 AC: 3464 AN: 152286 Hom.: 393 Cov.: 32 AF XY: 0.0254 AC XY: 1894 AN XY: 74444

African (AFR) AF: 0.00532 AC: 221 AN: 41548

American (AMR) AF: 0.0815 AC: 1247 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.323 AC: 1670 AN: 5176

South Asian (SAS) AF: 0.0347 AC: 167 AN: 4818

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00132 AC: 90 AN: 68022

Other (OTH) AF: 0.0279 AC: 59 AN: 2114

Alfa AF: 0.00274 Hom.: 9

Bravo AF: 0.0321

Asia WGS AF: 0.165 AC: 571 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00184

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	4.0
DANN	Benign	0.84
PhyloP100		3.3
Mutation Taster		=92/8	polymorphism (auto)

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: rs17010022; hg19: chr2-74763258; COSMIC: COSV51206163; COSMIC: COSV51206163;