NM_000302.4:c.1140C>T

Variant names:

• chr1-11963574-C-T
• rs200131516
• NM_000302.4:c.1140C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000302.4(PLOD1):​c.1140C>T​(p.Ser380Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,605,086 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: PLOD1 NM_000302.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -0.505
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 1-11963574-C-T is Benign according to our data. Variant chr1-11963574-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 264103.
• BP7: Synonymous conserved (PhyloP=-0.505 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.1140C>T	p.Ser380Ser	synonymous	Exon 11 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.1281C>T	p.Ser427Ser	synonymous	Exon 12 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.1140C>T	p.Ser380Ser	synonymous	Exon 11 of 19	ENSP00000196061.4	Q02809-1
	PLOD1	ENST00000854019.1		c.1284C>T	p.Ser428Ser	synonymous	Exon 12 of 20	ENSP00000524078.1
	PLOD1	ENST00000854031.1		c.1227C>T	p.Ser409Ser	synonymous	Exon 12 of 20	ENSP00000524090.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152174 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000162 AC: 38 AN: 234316 AF XY: 0.000182

Gnomad AFR exome AF: 0.0000676

Gnomad AMR exome AF: 0.000123

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.0000573

Gnomad FIN exome AF: 0.0000507

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000212 AC: 308 AN: 1452794 Hom.: 0 Cov.: 31 AF XY: 0.000227 AC XY: 164 AN XY: 721638

African (AFR) AF: 0.000209 AC: 7 AN: 33438

American (AMR) AF: 0.0000928 AC: 4 AN: 43118

Ashkenazi Jewish (ASJ) AF: 0.0000387 AC: 1 AN: 25834

East Asian (EAS) AF: 0.00 AC: 0 AN: 39392

South Asian (SAS) AF: 0.0000238 AC: 2 AN: 84148

European-Finnish (FIN) AF: 0.0000381 AC: 2 AN: 52544

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.000253 AC: 281 AN: 1108518

Other (OTH) AF: 0.000167 AC: 10 AN: 60044

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152292 Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13 AN XY: 74458

African (AFR) AF: 0.000192 AC: 8 AN: 41562

American (AMR) AF: 0.000131 AC: 2 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68010

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000141 Hom.: 0

Bravo AF: 0.000196

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Ehlers-Danlos syndrome, kyphoscoliotic type 1 (2)
-	1	-	Ehlers-Danlos syndrome (1)
-	-	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	Benign	-0.55
CADD	Benign	3.6
DANN	Benign	0.50
PhyloP100		-0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs200131516; hg19: chr1-12023631;