1-11949854-G-C

Position:

• chr1-11949854-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000302.4(PLOD1):​c.250G>C​(p.Ala84Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A84T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLOD1 NM_000302.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.06

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLOD1	NM_000302.4	c.250G>C	p.Ala84Pro	missense_variant	3/19	ENST00000196061.5	NP_000293.2
PLOD1	NM_001316320.2	c.391G>C	p.Ala131Pro	missense_variant	4/20		NP_001303249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLOD1	ENST00000196061.5	c.250G>C	p.Ala84Pro	missense_variant	3/19	1	NM_000302.4	ENSP00000196061.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;T;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.6	.;.;M
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Benign	0.29
Sift	Uncertain	0.010	D;D;D
Sift4G	Benign	0.11	T;T;T
Polyphen		0.96	.;.;D
Vest4		0.66
MutPred		0.46		Loss of ubiquitination at K134 (P = 0.0461);.;.;
MVP		0.82
MPC		0.55
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.73
gMVP		0.89

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: rs34878020; hg19: chr1-12009911;