chr1-11970702-G-T

Variant names:

• chr1-11970702-G-T
• rs35460537
• NM_000302.4:c.1788G>T

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.1788G>T​(p.Val596Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00725 in 1,613,122 control chromosomes in the GnomAD database, including 210 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (86 hom., cov: 27)
  • Exomes 𝑓: 0.0059 (124 hom.)
• Consequence: PLOD1 NM_000302.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.111
• 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, PanelApp Australia, G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 1-11970702-G-T is Benign according to our data. Variant chr1-11970702-G-T is described in ClinVar as Benign. ClinVar VariationId is 263892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.111 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0596 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.1788G>T	p.Val596Val	synonymous	Exon 17 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.1929G>T	p.Val643Val	synonymous	Exon 18 of 20	NP_001303249.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLOD1	ENST00000196061.5	TSL:1 MANE Select	c.1788G>T	p.Val596Val	synonymous	Exon 17 of 19	ENSP00000196061.4
	PLOD1	ENST00000854019.1		c.1932G>T	p.Val644Val	synonymous	Exon 18 of 20	ENSP00000524078.1
	PLOD1	ENST00000854031.1		c.1875G>T	p.Val625Val	synonymous	Exon 18 of 20	ENSP00000524090.1

Frequencies

GnomAD3 genomes AF: 0.0204 AC: 3096 AN: 151474 Hom.: 86 Cov.: 27

Gnomad AFR AF: 0.0616

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00967

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000198

Gnomad SAS AF: 0.0181

Gnomad FIN AF: 0.000568

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00419

Gnomad OTH AF: 0.0149

GnomAD2 exomes AF: 0.00937 AC: 2352 AN: 250972 AF XY: 0.00867

Gnomad AFR exome AF: 0.0655

Gnomad AMR exome AF: 0.00682

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00369

Gnomad OTH exome AF: 0.00702

GnomAD4 exome AF: 0.00588 AC: 8590 AN: 1461528 Hom.: 124 Cov.: 33 AF XY: 0.00601 AC XY: 4371 AN XY: 727068

African (AFR) AF: 0.0653 AC: 2186 AN: 33478

American (AMR) AF: 0.00711 AC: 318 AN: 44720

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

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.0172 AC: 1485 AN: 86258

European-Finnish (FIN) AF: 0.000640 AC: 34 AN: 53102

Middle Eastern (MID) AF: 0.0203 AC: 117 AN: 5768

European-Non Finnish (NFE) AF: 0.00352 AC: 3913 AN: 1111980

Other (OTH) AF: 0.00873 AC: 527 AN: 60388

GnomAD4 genome AF: 0.0205 AC: 3101 AN: 151594 Hom.: 86 Cov.: 27 AF XY: 0.0193 AC XY: 1430 AN XY: 74016

African (AFR) AF: 0.0616 AC: 2542 AN: 41254

American (AMR) AF: 0.00959 AC: 146 AN: 15222

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

East Asian (EAS) AF: 0.000198 AC: 1 AN: 5040

South Asian (SAS) AF: 0.0183 AC: 88 AN: 4796

European-Finnish (FIN) AF: 0.000568 AC: 6 AN: 10558

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

European-Non Finnish (NFE) AF: 0.00419 AC: 285 AN: 67946

Other (OTH) AF: 0.0147 AC: 31 AN: 2102

Alfa AF: 0.0108 Hom.: 25

Bravo AF: 0.0232

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00462

ClinVar

ClinVar submissions as Germline

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	-0.47
CADD	Benign	2.4
DANN	Benign	0.57
PhyloP100		0.11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs35460537; hg19: chr1-12030759;