rs35958757

Variant names:

• chr1-11952696-G-A
• rs35958757
• NM_000302.4:c.540G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000302.4(PLOD1):​c.540G>A​(p.Gln180Gln) variant causes a synonymous change. The variant allele was found at a frequency of 0.00352 in 1,614,034 control chromosomes in the GnomAD database, including 168 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (84 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (84 hom.)
• Consequence: PLOD1 NM_000302.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 6.89
• Publications: 5 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: Genomics England PanelApp, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 1-11952696-G-A is Benign according to our data. Variant chr1-11952696-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 292283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0582 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.540G>A	p.Gln180Gln	synonymous	Exon 5 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.681G>A	p.Gln227Gln	synonymous	Exon 6 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.540G>A	p.Gln180Gln	synonymous	Exon 5 of 19	ENSP00000196061.4	Q02809-1
	PLOD1	ENST00000854019.1		c.684G>A	p.Gln228Gln	synonymous	Exon 6 of 20	ENSP00000524078.1
	PLOD1	ENST00000854031.1		c.540G>A	p.Gln180Gln	synonymous	Exon 5 of 20	ENSP00000524090.1

Frequencies

GnomAD3 genomes AF: 0.0174 AC: 2653 AN: 152202 Hom.: 84 Cov.: 32

Gnomad AFR AF: 0.0601

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00494 AC: 1243 AN: 251404 AF XY: 0.00352

Gnomad AFR exome AF: 0.0620

Gnomad AMR exome AF: 0.00309

Gnomad ASJ exome AF: 0.00694

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00206 AC: 3017 AN: 1461714 Hom.: 84 Cov.: 31 AF XY: 0.00182 AC XY: 1320 AN XY: 727176

African (AFR) AF: 0.0626 AC: 2095 AN: 33466

American (AMR) AF: 0.00365 AC: 163 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00566 AC: 148 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00590 AC: 34 AN: 5766

European-Non Finnish (NFE) AF: 0.000268 AC: 298 AN: 1111886

Other (OTH) AF: 0.00449 AC: 271 AN: 60392

GnomAD4 genome AF: 0.0175 AC: 2662 AN: 152320 Hom.: 84 Cov.: 32 AF XY: 0.0166 AC XY: 1238 AN XY: 74502

African (AFR) AF: 0.0601 AC: 2499 AN: 41564

American (AMR) AF: 0.00529 AC: 81 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68032

Other (OTH) AF: 0.0137 AC: 29 AN: 2114

Alfa AF: 0.0103 Hom.: 25

Bravo AF: 0.0198

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Ehlers-Danlos syndrome, kyphoscoliotic type 1 (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	-0.45
CADD	Benign	5.9
DANN	Benign	0.93
PhyloP100		6.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=28/72	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35958757; hg19: chr1-12012753;