rs34032489

Variant names:

• chr1-11949781-C-T
• rs34032489
• NM_000302.4:c.177C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000302.4(PLOD1):​c.177C>T​(p.Gly59Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,613,860 control chromosomes in the GnomAD database, including 245 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (123 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (122 hom.)
• Consequence: PLOD1 NM_000302.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.126
• Publications: 0 publications found

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: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 1-11949781-C-T is Benign according to our data. Variant chr1-11949781-C-T is described in ClinVar as Benign. ClinVar VariationId is 263887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.126 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0829 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000302.4. 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
	PLOD1	NM_000302.4	MANE Select	c.177C>T	p.Gly59Gly	synonymous	Exon 3 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.318C>T	p.Gly106Gly	synonymous	Exon 4 of 20	NP_001303249.1	Q02809-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLOD1	ENST00000196061.5	TSL:1 MANE Select	c.177C>T	p.Gly59Gly	synonymous	Exon 3 of 19	ENSP00000196061.4	Q02809-1
	PLOD1	ENST00000854019.1		c.321C>T	p.Gly107Gly	synonymous	Exon 4 of 20	ENSP00000524078.1
	PLOD1	ENST00000854031.1		c.177C>T	p.Gly59Gly	synonymous	Exon 3 of 20	ENSP00000524090.1

Frequencies

GnomAD3 genomes AF: 0.0244 AC: 3709 AN: 152002 Hom.: 123 Cov.: 32

Gnomad AFR AF: 0.0853

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00735

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.00642 AC: 1613 AN: 251310 AF XY: 0.00467

Gnomad AFR exome AF: 0.0900

Gnomad AMR exome AF: 0.00280

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00243 AC: 3551 AN: 1461738 Hom.: 122 Cov.: 31 AF XY: 0.00202 AC XY: 1468 AN XY: 727174

African (AFR) AF: 0.0865 AC: 2895 AN: 33476

American (AMR) AF: 0.00338 AC: 151 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00256 AC: 67 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5760

European-Non Finnish (NFE) AF: 0.0000809 AC: 90 AN: 1111932

Other (OTH) AF: 0.00528 AC: 319 AN: 60390

GnomAD4 genome AF: 0.0244 AC: 3715 AN: 152122 Hom.: 123 Cov.: 32 AF XY: 0.0226 AC XY: 1679 AN XY: 74348

African (AFR) AF: 0.0852 AC: 3535 AN: 41482

American (AMR) AF: 0.00733 AC: 112 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68008

Other (OTH) AF: 0.0213 AC: 45 AN: 2114

Alfa AF: 0.0126 Hom.: 28

Bravo AF: 0.0276

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Ehlers-Danlos syndrome, kyphoscoliotic type 1 (3)
-	-	3	not specified (3)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.4
DANN	Benign	0.47
PhyloP100		-0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs34032489; hg19: chr1-12009838;