NM_000302.4:c.1206C>A

Variant names:

• chr1-11964178-C-A
• rs1130529
• NM_000302.4:c.1206C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000302.4(PLOD1):​c.1206C>A​(p.Asn402Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N402S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PLOD1 NM_000302.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.738
• Publications: 24 publications found

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 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome, kyphoscoliotic type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04275766).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000302.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLOD1	NM_000302.4	MANE Select	c.1206C>A	p.Asn402Lys	missense	Exon 12 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.1347C>A	p.Asn449Lys	missense	Exon 13 of 20	NP_001303249.1	Q02809-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLOD1	ENST00000196061.5	TSL:1 MANE Select	c.1206C>A	p.Asn402Lys	missense	Exon 12 of 19	ENSP00000196061.4	Q02809-1
	PLOD1	ENST00000854019.1		c.1350C>A	p.Asn450Lys	missense	Exon 13 of 20	ENSP00000524078.1
	PLOD1	ENST00000854031.1		c.1293C>A	p.Asn431Lys	missense	Exon 13 of 20	ENSP00000524090.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 12468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	7.0
DANN	Benign	0.75
DEOGEN2	Benign	0.032	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.46	N
PhyloP100		-0.74
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.24
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.011	B
Vest4		0.11
MVP		0.61
MPC		0.24
ClinPred		0.13	T
GERP RS		-5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.044
gMVP		0.51
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1130529; hg19: chr1-12024235;