rs2230898

chr1-11966298-A-Cchr1-11966298-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000302.4(PLOD1):c.1632A>C(p.Ala544=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0755 in 1,606,252 control chromosomes in the GnomAD database, including 5,095 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A544A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.058 (369 hom., cov: 28)
  • Exomes 𝑓: 0.077 (4726 hom.)
• Consequence: PLOD1 NM_000302.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.448

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-11966298-A-C is Benign according to our data. Variant chr1-11966298-A-C is described in ClinVar as [Benign]. Clinvar id is 255802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11966298-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.448 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLOD1	NM_000302.4	c.1632A>C	p.Ala544=	synonymous_variant	15/19	ENST00000196061.5
PLOD1	NM_001316320.2	c.1773A>C	p.Ala591=	synonymous_variant	16/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLOD1	ENST00000196061.5	c.1632A>C	p.Ala544=	synonymous_variant	15/19	1	NM_000302.4	P1
PLOD1	ENST00000470133.1	n.246A>C		non_coding_transcript_exon_variant	3/3	3
PLOD1	ENST00000491536.5	n.260A>C		non_coding_transcript_exon_variant	3/5	3

Frequencies

GnomAD3 genomes AF: 0.0581 AC: 8818 AN: 151662 Hom.: 368 Cov.: 28

Gnomad AFR AF: 0.0161

Gnomad AMI AF: 0.0714

Gnomad AMR AF: 0.0578

Gnomad ASJ AF: 0.0850

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.0637

Gnomad FIN AF: 0.0281

Gnomad MID AF: 0.0573

Gnomad NFE AF: 0.0832

Gnomad OTH AF: 0.0608

GnomAD3 exomes AF: 0.0618 AC: 14818 AN: 239912 Hom.: 560 AF XY: 0.0631 AC XY: 8197 AN XY: 129852

Gnomad AFR exome AF: 0.0139

Gnomad AMR exome AF: 0.0300

Gnomad ASJ exome AF: 0.0884

Gnomad EAS exome AF: 0.0968

Gnomad SAS exome AF: 0.0587

Gnomad FIN exome AF: 0.0316

Gnomad NFE exome AF: 0.0770

Gnomad OTH exome AF: 0.0603

GnomAD4 exome AF: 0.0773 AC: 112463 AN: 1454472 Hom.: 4726 Cov.: 32 AF XY: 0.0765 AC XY: 55328 AN XY: 722928

Gnomad4 AFR exome AF: 0.0122

Gnomad4 AMR exome AF: 0.0322

Gnomad4 ASJ exome AF: 0.0844

Gnomad4 EAS exome AF: 0.0827

Gnomad4 SAS exome AF: 0.0581

Gnomad4 FIN exome AF: 0.0323

Gnomad4 NFE exome AF: 0.0845

Gnomad4 OTH exome AF: 0.0766

GnomAD4 genome AF: 0.0581 AC: 8816 AN: 151780 Hom.: 369 Cov.: 28 AF XY: 0.0571 AC XY: 4234 AN XY: 74206

Gnomad4 AFR AF: 0.0161

Gnomad4 AMR AF: 0.0577

Gnomad4 ASJ AF: 0.0850

Gnomad4 EAS AF: 0.101

Gnomad4 SAS AF: 0.0640

Gnomad4 FIN AF: 0.0281

Gnomad4 NFE AF: 0.0832

Gnomad4 OTH AF: 0.0597

Alfa AF: 0.0736 Hom.: 172

Bravo AF: 0.0572

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2023	- -

Ehlers-Danlos syndrome, kyphoscoliotic type 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	2.0
Dann	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs2230898; hg19: chr1-12026355;