Genetic Variant PLOD1:n.119+236G>C (chr1-11934559-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000485046.5(PLOD1):n.119+236G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 578,078 control chromosomes in the GnomAD database, including 783 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.051 ( 643 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 140 hom. )

Consequence

PLOD1
ENST00000485046.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.34

Publications

0 publications found

Variant links:

Genes affected

PLOD1 (HGNC:9081): (procollagen-lysine,2-oxoglutarate 5-dioxygenase 1) Lysyl hydroxylase is a membrane-bound homodimeric protein localized to the cisternae of the endoplasmic reticulum. The enzyme (cofactors iron and ascorbate) catalyzes the hydroxylation of lysyl residues in collagen-like peptides. The resultant hydroxylysyl groups are attachment sites for carbohydrates in collagen and thus are critical for the stability of intermolecular crosslinks. Some patients with Ehlers-Danlos syndrome type VI have deficiencies in lysyl hydroxylase activity. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

PLOD1 Gene-Disease associations (from GenCC):

Ehlers-Danlos syndrome, kyphoscoliotic type 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, PanelApp Australia, G2P

PLOD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 1-11934559-G-C is Benign according to our data. Variant chr1-11934559-G-C is described in ClinVar as [Benign]. Clinvar id is 1261086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLOD1	NM_000302.4 link	c.-221G>C		upstream_gene_variant		ENST00000196061.5	NP_000293.2	Q02809-1
PLOD1	NM_001316320.2 link	c.-221G>C		upstream_gene_variant			NP_001303249.1	Q02809-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLOD1	ENST00000196061.5 link	c.-221G>C		upstream_gene_variant		1	NM_000302.4	ENSP00000196061.4		Q02809-1

Frequencies

GnomAD3 genomes

AF:

0.0510

AC:

7760

AN:

152142

Hom.:

637

Cov.:

show subpopulations

Gnomad AFR

AF:

0.177

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0189

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.0382

GnomAD4 exome

AF:

0.00457

AC:

1946

AN:

425818

Hom.:

140

AF XY:

0.00377

AC XY:

832

AN XY:

220598

show subpopulations

African (AFR)

AF:

0.171

AC:

1443

AN:

8432

American (AMR)

AF:

0.0129

AC:

AN:

7196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10796

East Asian (EAS)

AF:

0.0000456

AC:

AN:

21924

South Asian (SAS)

AF:

0.000271

AC:

AN:

33172

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26688

Middle Eastern (MID)

AF:

0.00690

AC:

AN:

1738

European-Non Finnish (NFE)

AF:

0.000236

AC:

AN:

292840

Other (OTH)

AF:

0.0139

AC:

319

AN:

23032

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

161

241

322

402

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0511

AC:

7787

AN:

152260

Hom.:

643

Cov.:

AF XY:

0.0492

AC XY:

3664

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.177

AC:

7368

AN:

41520

American (AMR)

AF:

0.0189

AC:

289

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000579

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000588

AC:

AN:

68030

Other (OTH)

AF:

0.0378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

330

660

991

1321

1651

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0295

Hom.:

Bravo

AF:

0.0577

Asia WGS

AF:

0.0220

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 26, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

2.7

(source)

DANN

Benign

0.47

PhyloP100

-1.3

PromoterAI

-0.010

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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1-11934559-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over