rs112250644

Positions:

• chr1-11965591-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_000302.4(PLOD1):​c.1582G>A​(p.Glu528Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000173 in 1,598,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: PLOD1 NM_000302.4 missense, splice_region
• Scores: Splicing: ADA: 0.0001462
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 4.63

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.016842455).
• BP6: Variant 1-11965591-G-A is Benign according to our data. Variant chr1-11965591-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 459811.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=3}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000775 (118/152304) while in subpopulation AFR AF= 0.00262 (109/41558). AF 95% confidence interval is 0.00222. There are 0 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLOD1	NM_000302.4	c.1582G>A	p.Glu528Lys	missense_variant, splice_region_variant	14/19	ENST00000196061.5
PLOD1	NM_001316320.2	c.1723G>A	p.Glu575Lys	missense_variant, splice_region_variant	15/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLOD1	ENST00000196061.5	c.1582G>A	p.Glu528Lys	missense_variant, splice_region_variant	14/19	1	NM_000302.4	P1
PLOD1	ENST00000470133.1	n.196G>A		splice_region_variant, non_coding_transcript_exon_variant	2/3	3
PLOD1	ENST00000491536.5	n.210G>A		splice_region_variant, non_coding_transcript_exon_variant	2/5	3

Frequencies

GnomAD3 genomes AF: 0.000775 AC: 118 AN: 152186 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000295 AC: 74 AN: 250438 Hom.: 0 AF XY: 0.000251 AC XY: 34 AN XY: 135528

Gnomad AFR exome AF: 0.00333

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.0000974

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000109 AC: 158 AN: 1445848 Hom.: 0 Cov.: 28 AF XY: 0.000101 AC XY: 73 AN XY: 720288

Gnomad4 AFR exome AF: 0.00304

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.0000200

Gnomad4 OTH exome AF: 0.000284

GnomAD4 genome AF: 0.000775 AC: 118 AN: 152304 Hom.: 0 Cov.: 31 AF XY: 0.000685 AC XY: 51 AN XY: 74474

Gnomad4 AFR AF: 0.00262

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000185 Hom.: 0

Bravo AF: 0.00108

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000412 AC: 50

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 18, 2022	BS1 -

Ehlers-Danlos syndrome, kyphoscoliotic type 1 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 29, 2021	The PLOD1 c.1582G>A; p.Glu528Lys variant (rs112250644), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 459811). This variant is found in the African/African-American population with an allele frequency of 0.27% (68/24928 alleles) in the Genome Aggregation Database. The glutamate at codon 528 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.537). Due to limited information, the clinical significance of the p.Glu528Lys variant is uncertain at this time. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 24, 2023

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 10, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.089
Eigen_PC	Benign	-0.031
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.50	N
REVEL	Uncertain	0.54
Sift	Benign	0.29	T
Sift4G	Benign	0.29	T
Polyphen		0.63	P
Vest4		0.69
MVP		0.89
MPC		0.23
ClinPred		0.012	T
GERP RS		4.6
Varity_R		0.10
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.0020
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: rs112250644; hg19: chr1-12025648; COSMIC: COSV105054981;