1-11950412-G-T

Position:

• chr1-11950412-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000302.4(PLOD1):​c.358G>T​(p.Ala120Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0898 in 1,613,908 control chromosomes in the GnomAD database, including 8,364 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A120A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (2124 hom., cov: 32)
  • Exomes 𝑓: 0.085 (6240 hom.)
• Consequence: PLOD1 NM_000302.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.32

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013234615).
• BP6: Variant 1-11950412-G-T is Benign according to our data. Variant chr1-11950412-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 255804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11950412-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLOD1	NM_000302.4	c.358G>T	p.Ala120Ser	missense_variant	4/19	ENST00000196061.5	NP_000293.2
PLOD1	NM_001316320.2	c.499G>T	p.Ala167Ser	missense_variant	5/20		NP_001303249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLOD1	ENST00000196061.5	c.358G>T	p.Ala120Ser	missense_variant	4/19	1	NM_000302.4	ENSP00000196061.4

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20682 AN: 152084 Hom.: 2119 Cov.: 32

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.0826

Gnomad ASJ AF: 0.0884

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.0635

Gnomad FIN AF: 0.0371

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0819

Gnomad OTH AF: 0.123

GnomAD3 exomes AF: 0.0867 AC: 21778 AN: 251224 Hom.: 1419 AF XY: 0.0824 AC XY: 11182 AN XY: 135772

Gnomad AFR exome AF: 0.293

Gnomad AMR exome AF: 0.0466

Gnomad ASJ exome AF: 0.0944

Gnomad EAS exome AF: 0.123

Gnomad SAS exome AF: 0.0591

Gnomad FIN exome AF: 0.0400

Gnomad NFE exome AF: 0.0800

Gnomad OTH exome AF: 0.0718

GnomAD4 exome AF: 0.0850 AC: 124277 AN: 1461706 Hom.: 6240 Cov.: 33 AF XY: 0.0831 AC XY: 60428 AN XY: 727176

Gnomad4 AFR exome AF: 0.287

Gnomad4 AMR exome AF: 0.0500

Gnomad4 ASJ exome AF: 0.0899

Gnomad4 EAS exome AF: 0.0941

Gnomad4 SAS exome AF: 0.0572

Gnomad4 FIN exome AF: 0.0403

Gnomad4 NFE exome AF: 0.0838

Gnomad4 OTH exome AF: 0.0964

GnomAD4 genome AF: 0.136 AC: 20715 AN: 152202 Hom.: 2124 Cov.: 32 AF XY: 0.133 AC XY: 9906 AN XY: 74428

Gnomad4 AFR AF: 0.287

Gnomad4 AMR AF: 0.0824

Gnomad4 ASJ AF: 0.0884

Gnomad4 EAS AF: 0.120

Gnomad4 SAS AF: 0.0638

Gnomad4 FIN AF: 0.0371

Gnomad4 NFE AF: 0.0819

Gnomad4 OTH AF: 0.121

Alfa AF: 0.0917 Hom.: 1770

Bravo AF: 0.145

TwinsUK AF: 0.0850 AC: 315

ALSPAC AF: 0.0867 AC: 334

ESP6500AA AF: 0.286 AC: 1261

ESP6500EA AF: 0.0836 AC: 719

ExAC AF: 0.0918 AC: 11149

Asia WGS AF: 0.0920 AC: 320 AN: 3478

EpiCase AF: 0.0808

EpiControl AF: 0.0856

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2023	- -

Ehlers-Danlos syndrome, kyphoscoliotic type 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2015

This alteration is classified as 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	.;T;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.82	T;T;T
MetaRNN	Benign	0.0013	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.77	.;.;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.69	N;N;N
REVEL	Benign	0.069
Sift	Benign	0.52	T;T;T
Sift4G	Benign	0.46	T;T;T
Polyphen		0.12	.;.;B
Vest4		0.083
MPC		0.20
ClinPred		0.024	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.040
gMVP		0.57

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: rs2273285; hg19: chr1-12010469;