chr1-11966298-A-C

Variant names:

• chr1-11966298-A-C
• rs2230898
• NM_000302.4:c.1632A>C

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.1632A>C​(p.Ala544Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0755 in 1,606,252 control chromosomes in the GnomAD database, including 5,095 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. A544A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.058 (369 hom., cov: 28)
  • Exomes 𝑓: 0.077 (4726 hom.)
• Consequence: PLOD1 NM_000302.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.448
• Publications: 9 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=-0.8).
• BP6: Variant 1-11966298-A-C is Benign according to our data. Variant chr1-11966298-A-C is described in ClinVar as Benign. ClinVar VariationId is 255802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.448 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0935 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.1632A>C	p.Ala544Ala	synonymous	Exon 15 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.1773A>C	p.Ala591Ala	synonymous	Exon 16 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.1632A>C	p.Ala544Ala	synonymous	Exon 15 of 19	ENSP00000196061.4	Q02809-1
	PLOD1	ENST00000854019.1		c.1776A>C	p.Ala592Ala	synonymous	Exon 16 of 20	ENSP00000524078.1
	PLOD1	ENST00000854031.1		c.1719A>C	p.Ala573Ala	synonymous	Exon 16 of 20	ENSP00000524090.1

Frequencies

GnomAD3 genomes AF: 0.0581 AC: 8818 AN: 151662 Hom.: 368 Cov.: 28

Gnomad AFR AF: 0.0161

Gnomad AMI AF: 0.0714

Gnomad AMR AF: 0.0578

Gnomad ASJ AF: 0.0850

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.0637

Gnomad FIN AF: 0.0281

Gnomad MID AF: 0.0573

Gnomad NFE AF: 0.0832

Gnomad OTH AF: 0.0608

GnomAD2 exomes AF: 0.0618 AC: 14818 AN: 239912 AF XY: 0.0631

Gnomad AFR exome AF: 0.0139

Gnomad AMR exome AF: 0.0300

Gnomad ASJ exome AF: 0.0884

Gnomad EAS exome AF: 0.0968

Gnomad FIN exome AF: 0.0316

Gnomad NFE exome AF: 0.0770

Gnomad OTH exome AF: 0.0603

GnomAD4 exome AF: 0.0773 AC: 112463 AN: 1454472 Hom.: 4726 Cov.: 32 AF XY: 0.0765 AC XY: 55328 AN XY: 722928

African (AFR) AF: 0.0122 AC: 406 AN: 33330

American (AMR) AF: 0.0322 AC: 1420 AN: 44130

Ashkenazi Jewish (ASJ) AF: 0.0844 AC: 2191 AN: 25954

East Asian (EAS) AF: 0.0827 AC: 3260 AN: 39432

South Asian (SAS) AF: 0.0581 AC: 4933 AN: 84920

European-Finnish (FIN) AF: 0.0323 AC: 1704 AN: 52724

Middle Eastern (MID) AF: 0.0444 AC: 256 AN: 5760

European-Non Finnish (NFE) AF: 0.0845 AC: 93685 AN: 1108104

Other (OTH) AF: 0.0766 AC: 4608 AN: 60118

GnomAD4 genome AF: 0.0581 AC: 8816 AN: 151780 Hom.: 369 Cov.: 28 AF XY: 0.0571 AC XY: 4234 AN XY: 74206

African (AFR) AF: 0.0161 AC: 668 AN: 41394

American (AMR) AF: 0.0577 AC: 878 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.0850 AC: 295 AN: 3470

East Asian (EAS) AF: 0.101 AC: 516 AN: 5128

South Asian (SAS) AF: 0.0640 AC: 306 AN: 4782

European-Finnish (FIN) AF: 0.0281 AC: 297 AN: 10586

Middle Eastern (MID) AF: 0.0514 AC: 15 AN: 292

European-Non Finnish (NFE) AF: 0.0832 AC: 5650 AN: 67886

Other (OTH) AF: 0.0597 AC: 126 AN: 2110

Alfa AF: 0.0736 Hom.: 172

Bravo AF: 0.0572

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Ehlers-Danlos syndrome, kyphoscoliotic type 1 (3)
-	-	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	-0.80
CADD	Benign	2.0
DANN	Benign	0.66
PhyloP100		-0.45
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: rs2230898; hg19: chr1-12026355;