1-11974757-C-G

Variant names:

• chr1-11974757-C-G
• rs879691
• NM_000302.4:c.2133C>G

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.2133C>G​(p.Leu711Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0072 in 1,614,006 control chromosomes in the GnomAD database, including 201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L711L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (81 hom., cov: 31)
  • Exomes 𝑓: 0.0058 (120 hom.)
• Consequence: PLOD1 NM_000302.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.711
• Publications: 3 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=-0.31).
• BP6: Variant 1-11974757-C-G is Benign according to our data. Variant chr1-11974757-C-G is described in ClinVar as Benign. ClinVar VariationId is 263889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.711 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0588 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.2133C>G	p.Leu711Leu	synonymous	Exon 19 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.2274C>G	p.Leu758Leu	synonymous	Exon 20 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.2133C>G	p.Leu711Leu	synonymous	Exon 19 of 19	ENSP00000196061.4	Q02809-1
	PLOD1	ENST00000854019.1		c.2277C>G	p.Leu759Leu	synonymous	Exon 20 of 20	ENSP00000524078.1
	PLOD1	ENST00000854031.1		c.2220C>G	p.Leu740Leu	synonymous	Exon 20 of 20	ENSP00000524090.1

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3080 AN: 152152 Hom.: 81 Cov.: 31

Gnomad AFR AF: 0.0608

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00956

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0182

Gnomad FIN AF: 0.000564

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00420

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.00927 AC: 2329 AN: 251334 AF XY: 0.00857

Gnomad AFR exome AF: 0.0646

Gnomad AMR exome AF: 0.00656

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00367

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.00584 AC: 8536 AN: 1461736 Hom.: 120 Cov.: 31 AF XY: 0.00598 AC XY: 4350 AN XY: 727186

African (AFR) AF: 0.0647 AC: 2165 AN: 33470

American (AMR) AF: 0.00684 AC: 306 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0172 AC: 1486 AN: 86252

European-Finnish (FIN) AF: 0.000637 AC: 34 AN: 53386

Middle Eastern (MID) AF: 0.0201 AC: 116 AN: 5768

European-Non Finnish (NFE) AF: 0.00351 AC: 3898 AN: 1111906

Other (OTH) AF: 0.00863 AC: 521 AN: 60394

GnomAD4 genome AF: 0.0203 AC: 3085 AN: 152270 Hom.: 81 Cov.: 31 AF XY: 0.0192 AC XY: 1428 AN XY: 74468

African (AFR) AF: 0.0608 AC: 2524 AN: 41540

American (AMR) AF: 0.00948 AC: 145 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0185 AC: 89 AN: 4820

European-Finnish (FIN) AF: 0.000564 AC: 6 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00421 AC: 286 AN: 68010

Other (OTH) AF: 0.0152 AC: 32 AN: 2112

Alfa AF: 0.00814 Hom.: 5

Bravo AF: 0.0229

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00462

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Ehlers-Danlos syndrome, kyphoscoliotic type 1 (3)
-	-	3	not specified (3)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	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	-0.31
CADD	Benign	8.3
DANN	Benign	0.70
PhyloP100		0.71
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: rs879691; hg19: chr1-12034814;