rs74354225

chr1-11957902-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000302.4(PLOD1):c.802A>G(p.Thr268Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000594 in 1,613,942 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T268N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0034 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (3 hom.)
• Consequence: PLOD1 NM_000302.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.857

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005416453).
• BP6: Variant 1-11957902-A-G is Benign according to our data. Variant chr1-11957902-A-G is described in ClinVar as [Benign]. Clinvar id is 440170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11957902-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00342 (521/152172) while in subpopulation AFR AF= 0.012 (500/41510). AF 95% confidence interval is 0.0112. There are 5 homozygotes in gnomad4. There are 229 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLOD1	NM_000302.4	c.802A>G	p.Thr268Ala	missense_variant	8/19	ENST00000196061.5
PLOD1	NM_001316320.2	c.943A>G	p.Thr315Ala	missense_variant	9/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLOD1	ENST00000196061.5	c.802A>G	p.Thr268Ala	missense_variant	8/19	1	NM_000302.4	P1
PLOD1	ENST00000429000.6	c.808A>G	p.Thr270Ala	missense_variant	8/8	5
PLOD1	ENST00000465920.1	n.752A>G		non_coding_transcript_exon_variant	3/4	5
PLOD1	ENST00000485046.5	n.845A>G		non_coding_transcript_exon_variant	8/9	5

Frequencies

GnomAD3 genomes AF: 0.00342 AC: 520 AN: 152054 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

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: 0.00430

GnomAD3 exomes AF: 0.000827 AC: 208 AN: 251440 Hom.: 2 AF XY: 0.000574 AC XY: 78 AN XY: 135896

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000299 AC: 437 AN: 1461770 Hom.: 3 Cov.: 31 AF XY: 0.000220 AC XY: 160 AN XY: 727208

Gnomad4 AFR exome AF: 0.0113

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.00342 AC: 521 AN: 152172 Hom.: 5 Cov.: 32 AF XY: 0.00308 AC XY: 229 AN XY: 74384

Gnomad4 AFR AF: 0.0120

Gnomad4 AMR AF: 0.000720

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: 0.00425

Alfa AF: 0.000604 Hom.: 0

Bravo AF: 0.00381

ESP6500AA AF: 0.0136 AC: 60

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00101 AC: 123

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Ehlers-Danlos syndrome, kyphoscoliotic type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 06, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	10
Dann	Benign	0.74
DEOGEN2	Benign	0.024	T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.75	T;T
MetaRNN	Benign	0.0054	T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.14
Sift	Benign	0.84	T;T
Sift4G	Benign	0.78	T;T
Polyphen		0.0	.;B
Vest4		0.13
MVP		0.47
MPC		0.20
ClinPred		0.0025	T
GERP RS		-0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.020
gMVP		0.59

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: rs74354225; hg19: chr1-12017959;