rs74949176

chr1-11963598-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000302.4(PLOD1):c.1164C>T(p.Thr388=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000342 in 1,602,802 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: PLOD1 NM_000302.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.74

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 1-11963598-C-T is Benign according to our data. Variant chr1-11963598-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 390574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11963598-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.74 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00162 (246/152262) while in subpopulation AFR AF= 0.00568 (236/41542). AF 95% confidence interval is 0.00509. There are 2 homozygotes in gnomad4. There are 117 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLOD1	NM_000302.4	c.1164C>T	p.Thr388=	synonymous_variant	11/19	ENST00000196061.5
PLOD1	NM_001316320.2	c.1305C>T	p.Thr435=	synonymous_variant	12/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLOD1	ENST00000196061.5	c.1164C>T	p.Thr388=	synonymous_variant	11/19	1	NM_000302.4	P1

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 246 AN: 152144 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00570

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000484 AC: 111 AN: 229396 Hom.: 0 AF XY: 0.000340 AC XY: 42 AN XY: 123710

Gnomad AFR exome AF: 0.00644

Gnomad AMR exome AF: 0.000315

Gnomad ASJ exome AF: 0.000105

Gnomad EAS exome AF: 0.000176

Gnomad SAS exome AF: 0.0000359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000289

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000208 AC: 302 AN: 1450540 Hom.: 1 Cov.: 31 AF XY: 0.000190 AC XY: 137 AN XY: 720348

Gnomad4 AFR exome AF: 0.00676

Gnomad4 AMR exome AF: 0.000305

Gnomad4 ASJ exome AF: 0.0000388

Gnomad4 EAS exome AF: 0.000229

Gnomad4 SAS exome AF: 0.000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000208

Gnomad4 OTH exome AF: 0.000283

GnomAD4 genome AF: 0.00162 AC: 246 AN: 152262 Hom.: 2 Cov.: 31 AF XY: 0.00157 AC XY: 117 AN XY: 74444

Gnomad4 AFR AF: 0.00568

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000801 Hom.: 0

Bravo AF: 0.00203

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 21, 2023

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Ehlers-Danlos syndrome, kyphoscoliotic type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	0.012
Dann	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs74949176; hg19: chr1-12023655;