rs199946373

Variant names:

• chr1-11958569-G-A
• rs199946373
• NM_000302.4:c.897G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-11958569-G-A
• chr1-11958569-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6 BP7

The NM_000302.4(PLOD1):​c.897G>A​(p.Pro299Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,614,000 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P299P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: PLOD1 NM_000302.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -1.95
• 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: Genomics England PanelApp, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 1-11958569-G-A is Benign according to our data. Variant chr1-11958569-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 459834.
• BP7: Synonymous conserved (PhyloP=-1.95 with no splicing effect.

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.897G>A	p.Pro299Pro	synonymous	Exon 9 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.1038G>A	p.Pro346Pro	synonymous	Exon 10 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.897G>A	p.Pro299Pro	synonymous	Exon 9 of 19	ENSP00000196061.4	Q02809-1
	PLOD1	ENST00000854019.1		c.1041G>A	p.Pro347Pro	synonymous	Exon 10 of 20	ENSP00000524078.1
	PLOD1	ENST00000854031.1		c.984G>A	p.Pro328Pro	synonymous	Exon 10 of 20	ENSP00000524090.1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152122 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000303 AC: 76 AN: 251068 AF XY: 0.000339

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00616

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000183 AC: 268 AN: 1461760 Hom.: 1 Cov.: 33 AF XY: 0.000198 AC XY: 144 AN XY: 727180

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000447 AC: 2 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00727 AC: 190 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

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

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1111948

Other (OTH) AF: 0.000613 AC: 37 AN: 60390

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152240 Hom.: 0 Cov.: 31 AF XY: 0.000107 AC XY: 8 AN XY: 74436

African (AFR) AF: 0.00 AC: 0 AN: 41540

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000743 Hom.: 0

Bravo AF: 0.000193

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Ehlers-Danlos syndrome, kyphoscoliotic type 1 (2)
-	-	2	not provided (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	not specified (1)
-	-	1	PLOD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	13
DANN	Benign	0.74
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs199946373; hg19: chr1-12018626; COSMIC: COSV52150550; COSMIC: COSV52150550;