rs777957649

Variant names:

• chr1-11958532-C-T
• rs777957649
• NM_000302.4:c.860C>T

Variant summary

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

The NM_001316320.2(PLOD1):​c.1001C>T​(p.Thr334Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T334T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: PLOD1 NM_001316320.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.157
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, PanelApp Australia, G2P

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=0.062938005).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001316320.2. 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.860C>T	p.Thr287Met	missense	Exon 9 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.1001C>T	p.Thr334Met	missense	Exon 10 of 20	NP_001303249.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLOD1	ENST00000196061.5	TSL:1 MANE Select	c.860C>T	p.Thr287Met	missense	Exon 9 of 19	ENSP00000196061.4
	PLOD1	ENST00000854019.1		c.1004C>T	p.Thr335Met	missense	Exon 10 of 20	ENSP00000524078.1
	PLOD1	ENST00000854031.1		c.947C>T	p.Thr316Met	missense	Exon 10 of 20	ENSP00000524090.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152160 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250158 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461510 Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8 AN XY: 727044

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111900

Other (OTH) AF: 0.0000331 AC: 2 AN: 60386

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152160 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74334

African (AFR) AF: 0.0000483 AC: 2 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Ehlers-Danlos syndrome, kyphoscoliotic type 1 (1)
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.7
DANN	Benign	0.96
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.16
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.035
Sift	Benign	0.13	T
Sift4G	Benign	0.11	T
Polyphen		0.0020	B
Vest4		0.31
MVP		0.43
MPC		0.22
ClinPred		0.046	T
GERP RS		-0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.011
gMVP		0.56
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs777957649; hg19: chr1-12018589;