chr1-11949898-C-T

Variant names:

• chr1-11949898-C-T
• rs7529452
• NM_000302.4:c.294C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000302.4(PLOD1):​c.294C>T​(p.Phe98Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,613,408 control chromosomes in the GnomAD database, including 82,689 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6299 hom., cov: 32)
  • Exomes 𝑓: 0.32 (76390 hom.)
• Consequence: PLOD1 NM_000302.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.08
• Publications: 27 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 1-11949898-C-T is Benign according to our data. Variant chr1-11949898-C-T is described in ClinVar as Benign. ClinVar VariationId is 255803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.415 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.294C>T	p.Phe98Phe	synonymous	Exon 3 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.435C>T	p.Phe145Phe	synonymous	Exon 4 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.294C>T	p.Phe98Phe	synonymous	Exon 3 of 19	ENSP00000196061.4	Q02809-1
	PLOD1	ENST00000854019.1		c.438C>T	p.Phe146Phe	synonymous	Exon 4 of 20	ENSP00000524078.1
	PLOD1	ENST00000854031.1		c.294C>T	p.Phe98Phe	synonymous	Exon 3 of 20	ENSP00000524090.1

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38595 AN: 151958 Hom.: 6298 Cov.: 32

Gnomad AFR AF: 0.0637

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.432

Gnomad FIN AF: 0.437

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.274

GnomAD2 exomes AF: 0.329 AC: 82814 AN: 251354 AF XY: 0.336

Gnomad AFR exome AF: 0.0589

Gnomad AMR exome AF: 0.352

Gnomad ASJ exome AF: 0.220

Gnomad EAS exome AF: 0.375

Gnomad FIN exome AF: 0.446

Gnomad NFE exome AF: 0.316

Gnomad OTH exome AF: 0.331

GnomAD4 exome AF: 0.317 AC: 463265 AN: 1461332 Hom.: 76390 Cov.: 36 AF XY: 0.321 AC XY: 233607 AN XY: 726970

African (AFR) AF: 0.0541 AC: 1812 AN: 33476

American (AMR) AF: 0.351 AC: 15692 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 5760 AN: 26134

East Asian (EAS) AF: 0.343 AC: 13604 AN: 39698

South Asian (SAS) AF: 0.428 AC: 36914 AN: 86248

European-Finnish (FIN) AF: 0.446 AC: 23806 AN: 53394

Middle Eastern (MID) AF: 0.310 AC: 1787 AN: 5766

European-Non Finnish (NFE) AF: 0.311 AC: 345222 AN: 1111516

Other (OTH) AF: 0.309 AC: 18668 AN: 60384

GnomAD4 genome AF: 0.254 AC: 38608 AN: 152076 Hom.: 6299 Cov.: 32 AF XY: 0.262 AC XY: 19467 AN XY: 74308

African (AFR) AF: 0.0635 AC: 2637 AN: 41542

American (AMR) AF: 0.289 AC: 4418 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 747 AN: 3472

East Asian (EAS) AF: 0.378 AC: 1947 AN: 5154

South Asian (SAS) AF: 0.431 AC: 2075 AN: 4818

European-Finnish (FIN) AF: 0.437 AC: 4605 AN: 10544

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.315 AC: 21391 AN: 67964

Other (OTH) AF: 0.277 AC: 585 AN: 2112

Alfa AF: 0.289 Hom.: 12124

Bravo AF: 0.231

Asia WGS AF: 0.390 AC: 1354 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	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	-0.41
CADD	Benign	13
DANN	Benign	0.82
PhyloP100		1.1
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: rs7529452; hg19: chr1-12009955; COSMIC: COSV52144592; COSMIC: COSV52144592;