rs142978362

Variant names:

• chr1-11952711-G-T
• rs142978362
• NM_000302.4:c.555G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-11952711-G-T
• chr1-11952711-G-A
• chr1-11952711-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000302.4(PLOD1):​c.555G>T​(p.Lys185Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00435 in 1,613,646 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K185R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (27 hom.)
• Consequence: PLOD1 NM_000302.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.59
• Publications: 8 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009829432).
• BP6: Variant 1-11952711-G-T is Benign according to our data. Variant chr1-11952711-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00274 (418/152330) while in subpopulation NFE AF = 0.00519 (353/68042). AF 95% confidence interval is 0.00474. There are 1 homozygotes in GnomAd4. There are 179 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 27 AR gene

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.555G>T	p.Lys185Asn	missense	Exon 5 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.696G>T	p.Lys232Asn	missense	Exon 6 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.555G>T	p.Lys185Asn	missense	Exon 5 of 19	ENSP00000196061.4	Q02809-1
	PLOD1	ENST00000854019.1		c.699G>T	p.Lys233Asn	missense	Exon 6 of 20	ENSP00000524078.1
	PLOD1	ENST00000854031.1		c.555G>T	p.Lys185Asn	missense	Exon 5 of 20	ENSP00000524090.1

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 419 AN: 152212 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00519

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00281 AC: 707 AN: 251332 AF XY: 0.00272

Gnomad AFR exome AF: 0.000985

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000740

Gnomad NFE exome AF: 0.00552

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00452 AC: 6609 AN: 1461316 Hom.: 27 Cov.: 30 AF XY: 0.00431 AC XY: 3133 AN XY: 727000

African (AFR) AF: 0.000866 AC: 29 AN: 33470

American (AMR) AF: 0.000939 AC: 42 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.000899 AC: 48 AN: 53394

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

European-Non Finnish (NFE) AF: 0.00560 AC: 6230 AN: 1111520

Other (OTH) AF: 0.00421 AC: 254 AN: 60370

GnomAD4 genome AF: 0.00274 AC: 418 AN: 152330 Hom.: 1 Cov.: 32 AF XY: 0.00240 AC XY: 179 AN XY: 74490

African (AFR) AF: 0.000986 AC: 41 AN: 41566

American (AMR) AF: 0.00105 AC: 16 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00519 AC: 353 AN: 68042

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00413 Hom.: 8

Bravo AF: 0.00271

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00628 AC: 54

ExAC AF: 0.00282 AC: 343

EpiCase AF: 0.00643

EpiControl AF: 0.00433

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Ehlers-Danlos syndrome, kyphoscoliotic type 1 (3)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.065
Eigen_PC	Benign	0.059
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.0098	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.6
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.041
Sift	Benign	0.075	T
Sift4G	Benign	0.067	T
Polyphen		0.0020	B
Vest4		0.31
MVP		0.62
MPC		0.25
ClinPred		0.026	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.77
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs142978362; hg19: chr1-12012768;