chr1-11967043-G-A

Variant names:

• chr1-11967043-G-A
• rs139468110
• NM_000302.4:c.1707G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_000302.4(PLOD1):​c.1707G>A​(p.Leu569Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,614,036 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: PLOD1 NM_000302.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.51
• 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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 1-11967043-G-A is Benign according to our data. Variant chr1-11967043-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 459816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.51 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000335 (51/152320) while in subpopulation AMR AF = 0.000915 (14/15302). AF 95% confidence interval is 0.000553. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1707G>A	p.Leu569Leu	synonymous	Exon 16 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.1848G>A	p.Leu616Leu	synonymous	Exon 17 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.1707G>A	p.Leu569Leu	synonymous	Exon 16 of 19	ENSP00000196061.4	Q02809-1
	PLOD1	ENST00000854019.1		c.1851G>A	p.Leu617Leu	synonymous	Exon 17 of 20	ENSP00000524078.1
	PLOD1	ENST00000854031.1		c.1794G>A	p.Leu598Leu	synonymous	Exon 17 of 20	ENSP00000524090.1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000191 AC: 48 AN: 251434 AF XY: 0.000213

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000152 AC: 222 AN: 1461716 Hom.: 0 Cov.: 31 AF XY: 0.000143 AC XY: 104 AN XY: 727174

African (AFR) AF: 0.000687 AC: 23 AN: 33478

American (AMR) AF: 0.000380 AC: 17 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000130 AC: 145 AN: 1111850

Other (OTH) AF: 0.000497 AC: 30 AN: 60392

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74474

African (AFR) AF: 0.000577 AC: 24 AN: 41572

American (AMR) AF: 0.000915 AC: 14 AN: 15302

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000147 Hom.: 0

Bravo AF: 0.000397

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	7.6
DANN	Benign	0.83
PhyloP100		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs139468110; hg19: chr1-12027100;