1-11934703-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000449038.5(PLOD1):c.-77G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00919 in 1,496,368 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0062 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (91 hom.)
• Consequence: PLOD1 ENST00000449038.5 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.496

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 1-11934703-G-A is Benign according to our data. Variant chr1-11934703-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 292249.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00624 (950/152300) while in subpopulation NFE AF= 0.0113 (769/68006). AF 95% confidence interval is 0.0106. There are 7 homozygotes in gnomad4. There are 408 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLOD1	NM_000302.4			upstream_gene_variant		ENST00000196061.5
PLOD1	NM_001316320.2			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLOD1	ENST00000196061.5			upstream_gene_variant		1	NM_000302.4	P1

Frequencies

GnomAD3 genomes AF: 0.00624 AC: 950 AN: 152186 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.00431

GnomAD4 exome AF: 0.00952 AC: 12802 AN: 1344068 Hom.: 91 Cov.: 31 AF XY: 0.00927 AC XY: 6144 AN XY: 662570

Gnomad4 AFR exome AF: 0.00162

Gnomad4 AMR exome AF: 0.00501

Gnomad4 ASJ exome AF: 0.00283

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.00189

Gnomad4 NFE exome AF: 0.0113

Gnomad4 OTH exome AF: 0.00723

GnomAD4 genome AF: 0.00624 AC: 950 AN: 152300 Hom.: 7 Cov.: 32 AF XY: 0.00548 AC XY: 408 AN XY: 74464

Gnomad4 AFR AF: 0.00209

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.0113

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00826 Hom.: 1

Bravo AF: 0.00675

Asia WGS AF: 0.000579 AC: 2 AN: 3470

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ehlers-Danlos syndrome, kyphoscoliotic type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

PLOD1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	16
Dann	Uncertain	0.98

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs144465849; hg19: chr1-11994760;