rs372579008

Variant names:

• chr1-11970732-C-A
• rs372579008
• NM_000302.4:c.1818C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-11970732-C-A
• chr1-11970732-C-G
• chr1-11970732-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6 BP7

The NM_001316320.2(PLOD1):​c.1959C>A​(p.Ile653Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,612,414 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I653I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000080 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: PLOD1 NM_001316320.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.0760
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, PanelApp Australia, G2P

ACMG classification

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

• BP6: Variant 1-11970732-C-A is Benign according to our data. Variant chr1-11970732-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 292342.
• BP7: Synonymous conserved (PhyloP=0.076 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001316320.2. 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.1818C>A	p.Ile606Ile	synonymous	Exon 17 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.1959C>A	p.Ile653Ile	synonymous	Exon 18 of 20	NP_001303249.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLOD1	ENST00000196061.5	TSL:1 MANE Select	c.1818C>A	p.Ile606Ile	synonymous	Exon 17 of 19	ENSP00000196061.4
	PLOD1	ENST00000854019.1		c.1962C>A	p.Ile654Ile	synonymous	Exon 18 of 20	ENSP00000524078.1
	PLOD1	ENST00000854031.1		c.1905C>A	p.Ile635Ile	synonymous	Exon 18 of 20	ENSP00000524090.1

Frequencies

GnomAD3 genomes AF: 0.0000795 AC: 12 AN: 150920 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000108 AC: 27 AN: 250938 AF XY: 0.000125

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000127 AC: 186 AN: 1461494 Hom.: 0 Cov.: 33 AF XY: 0.000128 AC XY: 93 AN XY: 727040

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000224 AC: 10 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000149 AC: 166 AN: 1111952

Other (OTH) AF: 0.000132 AC: 8 AN: 60384

GnomAD4 genome AF: 0.0000795 AC: 12 AN: 150920 Hom.: 0 Cov.: 27 AF XY: 0.0000816 AC XY: 6 AN XY: 73534

African (AFR) AF: 0.00 AC: 0 AN: 40920

American (AMR) AF: 0.000198 AC: 3 AN: 15128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5022

South Asian (SAS) AF: 0.00 AC: 0 AN: 4760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000133 AC: 9 AN: 67862

Other (OTH) AF: 0.00 AC: 0 AN: 2062

Alfa AF: 0.000152 Hom.: 0

Bravo AF: 0.000110

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

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	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	12
DANN	Benign	0.77
PhyloP100		0.076
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=84/16	polymorphism

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: rs372579008; hg19: chr1-12030789;