rs138490756

Variant names:

• chr1-11965543-C-T
• rs138490756
• NM_000302.4:c.1534C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-11965543-C-T
• chr1-11965543-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000302.4(PLOD1):​c.1534C>T​(p.Arg512Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00474 in 1,613,664 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R512H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0049 (27 hom.)
• Consequence: PLOD1 NM_000302.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 0.357
• Publications: 12 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013092965).
• BP6: Variant 1-11965543-C-T is Benign according to our data. Variant chr1-11965543-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255801.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00321 (489/152270) while in subpopulation NFE AF = 0.00572 (389/68024). AF 95% confidence interval is 0.00525. There are 2 homozygotes in GnomAd4. There are 205 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.1534C>T	p.Arg512Cys	missense	Exon 14 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.1675C>T	p.Arg559Cys	missense	Exon 15 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.1534C>T	p.Arg512Cys	missense	Exon 14 of 19	ENSP00000196061.4	Q02809-1
	PLOD1	ENST00000854019.1		c.1678C>T	p.Arg560Cys	missense	Exon 15 of 20	ENSP00000524078.1
	PLOD1	ENST00000854031.1		c.1621C>T	p.Arg541Cys	missense	Exon 15 of 20	ENSP00000524090.1

Frequencies

GnomAD3 genomes AF: 0.00323 AC: 491 AN: 152152 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00573

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00312 AC: 784 AN: 251210 AF XY: 0.00332

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00226

Gnomad NFE exome AF: 0.00486

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00490 AC: 7156 AN: 1461394 Hom.: 27 Cov.: 31 AF XY: 0.00487 AC XY: 3538 AN XY: 726980

African (AFR) AF: 0.000418 AC: 14 AN: 33470

American (AMR) AF: 0.000850 AC: 38 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00207 AC: 54 AN: 26134

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

South Asian (SAS) AF: 0.00349 AC: 301 AN: 86254

European-Finnish (FIN) AF: 0.00280 AC: 149 AN: 53146

Middle Eastern (MID) AF: 0.0104 AC: 60 AN: 5768

European-Non Finnish (NFE) AF: 0.00566 AC: 6289 AN: 1111822

Other (OTH) AF: 0.00416 AC: 251 AN: 60380

GnomAD4 genome AF: 0.00321 AC: 489 AN: 152270 Hom.: 2 Cov.: 31 AF XY: 0.00275 AC XY: 205 AN XY: 74454

African (AFR) AF: 0.000890 AC: 37 AN: 41556

American (AMR) AF: 0.00157 AC: 24 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4824

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10612

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00572 AC: 389 AN: 68024

Other (OTH) AF: 0.00237 AC: 5 AN: 2106

Alfa AF: 0.00426 Hom.: 6

Bravo AF: 0.00294

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00344 AC: 417

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00518

EpiControl AF: 0.00528

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Ehlers-Danlos syndrome, kyphoscoliotic type 1 (4)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.36
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.94	P
Vest4		0.43
MVP		0.86
MPC		0.42
ClinPred		0.030	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.64
Mutation Taster		=95/5	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: rs138490756; hg19: chr1-12025600;