rs1130529

Variant names:

• chr1-11964178-C-T
• rs1130529
• NM_000302.4:c.1206C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-11964178-C-T
• chr1-11964178-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000302.4(PLOD1):​c.1206C>T​(p.Asn402Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.336 in 1,612,832 control chromosomes in the GnomAD database, including 93,783 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8723 hom., cov: 31)
  • Exomes 𝑓: 0.34 (85060 hom.)
• Consequence: PLOD1 NM_000302.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.738
• Publications: 24 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 1-11964178-C-T is Benign according to our data. Variant chr1-11964178-C-T is described in ClinVar as Benign. ClinVar VariationId is 255799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.738 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.435 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.1206C>T	p.Asn402Asn	synonymous	Exon 12 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.1347C>T	p.Asn449Asn	synonymous	Exon 13 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.1206C>T	p.Asn402Asn	synonymous	Exon 12 of 19	ENSP00000196061.4	Q02809-1
	PLOD1	ENST00000854019.1		c.1350C>T	p.Asn450Asn	synonymous	Exon 13 of 20	ENSP00000524078.1
	PLOD1	ENST00000854031.1		c.1293C>T	p.Asn431Asn	synonymous	Exon 13 of 20	ENSP00000524090.1

Frequencies

GnomAD3 genomes AF: 0.331 AC: 50294 AN: 151856 Hom.: 8715 Cov.: 31

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.450

Gnomad FIN AF: 0.497

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.325

Gnomad OTH AF: 0.325

GnomAD2 exomes AF: 0.361 AC: 90668 AN: 251250 AF XY: 0.364

Gnomad AFR exome AF: 0.293

Gnomad AMR exome AF: 0.367

Gnomad ASJ exome AF: 0.224

Gnomad EAS exome AF: 0.390

Gnomad FIN exome AF: 0.501

Gnomad NFE exome AF: 0.327

Gnomad OTH exome AF: 0.358

GnomAD4 exome AF: 0.336 AC: 491381 AN: 1460858 Hom.: 85060 Cov.: 39 AF XY: 0.340 AC XY: 246803 AN XY: 726778

African (AFR) AF: 0.294 AC: 9824 AN: 33470

American (AMR) AF: 0.367 AC: 16405 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 5855 AN: 26132

East Asian (EAS) AF: 0.363 AC: 14428 AN: 39694

South Asian (SAS) AF: 0.448 AC: 38664 AN: 86242

European-Finnish (FIN) AF: 0.501 AC: 26670 AN: 53214

Middle Eastern (MID) AF: 0.328 AC: 1892 AN: 5768

European-Non Finnish (NFE) AF: 0.321 AC: 357104 AN: 1111262

Other (OTH) AF: 0.340 AC: 20539 AN: 60356

GnomAD4 genome AF: 0.331 AC: 50336 AN: 151974 Hom.: 8723 Cov.: 31 AF XY: 0.340 AC XY: 25216 AN XY: 74254

African (AFR) AF: 0.295 AC: 12222 AN: 41446

American (AMR) AF: 0.320 AC: 4884 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 748 AN: 3472

East Asian (EAS) AF: 0.396 AC: 2041 AN: 5158

South Asian (SAS) AF: 0.450 AC: 2171 AN: 4820

European-Finnish (FIN) AF: 0.497 AC: 5247 AN: 10558

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.325 AC: 22095 AN: 67932

Other (OTH) AF: 0.328 AC: 694 AN: 2114

Alfa AF: 0.323 Hom.: 12468

Bravo AF: 0.315

Asia WGS AF: 0.426 AC: 1482 AN: 3478

EpiCase AF: 0.309

EpiControl AF: 0.304

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	Ehlers-Danlos syndrome, kyphoscoliotic type 1 (4)
-	-	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	-0.53
CADD	Benign	6.9
DANN	Benign	0.75
PhyloP100		-0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs1130529; hg19: chr1-12024235; COSMIC: COSV52140468; COSMIC: COSV52140468;