2-74552556-G-C

Variant names:

• chr2-74552556-G-C
• rs146972503
• NM_032603.5:c.79C>G

Variant summary

Our verdict is Benign. The variant received -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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P27L) has been classified as Uncertain significance.

• 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
• Publications: 1 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]

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

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 262092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR,Unknown gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXL3	NM_032603.5	MANE Select	c.79C>G	p.Pro27Ala	missense	Exon 2 of 14	NP_115992.1
	LOXL3	NM_001289164.3		c.79C>G	p.Pro27Ala	missense	Exon 2 of 12	NP_001276093.1
	DOK1	NM_001197260.2		c.-357-2598G>C		intron	N/A	NP_001184189.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LOXL3	ENST00000264094.8	TSL:1 MANE Select	c.79C>G	p.Pro27Ala	missense	Exon 2 of 14	ENSP00000264094.3
	DOK1	ENST00000409429.5	TSL:1	c.-357-2598G>C		intron	N/A	ENSP00000387016.1
	LOXL3	ENST00000409549.5	TSL:2	c.79C>G	p.Pro27Ala	missense	Exon 1 of 12	ENSP00000386696.1

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

GnomAD2 exomes AF: 0.00214 AC: 520 AN: 242750 AF XY: 0.00228

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 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

African (AFR) AF: 0.000628 AC: 21 AN: 33450

American (AMR) AF: 0.000898 AC: 40 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00107 AC: 92 AN: 86072

European-Finnish (FIN) AF: 0.00345 AC: 181 AN: 52516

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5764

European-Non Finnish (NFE) AF: 0.00315 AC: 3504 AN: 1111156

Other (OTH) AF: 0.00234 AC: 141 AN: 60280

GnomAD4 genome AF: 0.00228 AC: 347 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.00230 AC XY: 171 AN XY: 74494

African (AFR) AF: 0.000649 AC: 27 AN: 41582

American (AMR) AF: 0.000914 AC: 14 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4828

European-Finnish (FIN) AF: 0.00395 AC: 42 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00367 AC: 250 AN: 68032

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

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

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DOK1: BS2; LOXL3: BP4, BS2

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.063
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.81	L
PhyloP100		1.4
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.067
Sift	Benign	0.21	T
Sift4G	Benign	0.20	T
Polyphen		0.13	B
Vest4		0.25
MVP		0.42
MPC		1.2
ClinPred		0.011	T
GERP RS		4.8
PromoterAI		0.0056	Neutral
Varity_R		0.098
gMVP		0.56
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs146972503; hg19: chr2-74779683;