rs2273285

Variant names:

• chr1-11950412-G-T
• rs2273285
• NM_000302.4:c.358G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-11950412-G-T
• chr1-11950412-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000302.4(PLOD1):​c.358G>T​(p.Ala120Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0898 in 1,613,908 control chromosomes in the GnomAD database, including 8,364 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. A120G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.14 (2124 hom., cov: 32)
  • Exomes 𝑓: 0.085 (6240 hom.)
• Consequence: PLOD1 NM_000302.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.32
• Publications: 19 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=0.0013234615).
• BP6: Variant 1-11950412-G-T is Benign according to our data. Variant chr1-11950412-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

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.358G>T	p.Ala120Ser	missense	Exon 4 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.499G>T	p.Ala167Ser	missense	Exon 5 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.358G>T	p.Ala120Ser	missense	Exon 4 of 19	ENSP00000196061.4	Q02809-1
	PLOD1	ENST00000854019.1		c.502G>T	p.Ala168Ser	missense	Exon 5 of 20	ENSP00000524078.1
	PLOD1	ENST00000854031.1		c.358G>T	p.Ala120Ser	missense	Exon 4 of 20	ENSP00000524090.1

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20682 AN: 152084 Hom.: 2119 Cov.: 32

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.0826

Gnomad ASJ AF: 0.0884

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.0635

Gnomad FIN AF: 0.0371

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0819

Gnomad OTH AF: 0.123

GnomAD2 exomes AF: 0.0867 AC: 21778 AN: 251224 AF XY: 0.0824

Gnomad AFR exome AF: 0.293

Gnomad AMR exome AF: 0.0466

Gnomad ASJ exome AF: 0.0944

Gnomad EAS exome AF: 0.123

Gnomad FIN exome AF: 0.0400

Gnomad NFE exome AF: 0.0800

Gnomad OTH exome AF: 0.0718

GnomAD4 exome AF: 0.0850 AC: 124277 AN: 1461706 Hom.: 6240 Cov.: 33 AF XY: 0.0831 AC XY: 60428 AN XY: 727176

African (AFR) AF: 0.287 AC: 9595 AN: 33470

American (AMR) AF: 0.0500 AC: 2236 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0899 AC: 2350 AN: 26134

East Asian (EAS) AF: 0.0941 AC: 3737 AN: 39700

South Asian (SAS) AF: 0.0572 AC: 4935 AN: 86258

European-Finnish (FIN) AF: 0.0403 AC: 2155 AN: 53416

Middle Eastern (MID) AF: 0.0562 AC: 324 AN: 5762

European-Non Finnish (NFE) AF: 0.0838 AC: 93126 AN: 1111854

Other (OTH) AF: 0.0964 AC: 5819 AN: 60390

GnomAD4 genome AF: 0.136 AC: 20715 AN: 152202 Hom.: 2124 Cov.: 32 AF XY: 0.133 AC XY: 9906 AN XY: 74428

African (AFR) AF: 0.287 AC: 11904 AN: 41516

American (AMR) AF: 0.0824 AC: 1260 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0884 AC: 307 AN: 3472

East Asian (EAS) AF: 0.120 AC: 622 AN: 5178

South Asian (SAS) AF: 0.0638 AC: 308 AN: 4828

European-Finnish (FIN) AF: 0.0371 AC: 394 AN: 10614

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0819 AC: 5569 AN: 67990

Other (OTH) AF: 0.121 AC: 255 AN: 2108

Alfa AF: 0.0987 Hom.: 4280

Bravo AF: 0.145

TwinsUK AF: 0.0850 AC: 315

ALSPAC AF: 0.0867 AC: 334

ESP6500AA AF: 0.286 AC: 1261

ESP6500EA AF: 0.0836 AC: 719

ExAC AF: 0.0918 AC: 11149

Asia WGS AF: 0.0920 AC: 320 AN: 3478

EpiCase AF: 0.0808

EpiControl AF: 0.0856

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	Ehlers-Danlos syndrome, kyphoscoliotic type 1 (3)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.77	N
PhyloP100		2.3
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.069
Sift	Benign	0.52	T
Sift4G	Benign	0.46	T
Polyphen		0.12	B
Vest4		0.083
MPC		0.20
ClinPred		0.024	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.040
gMVP		0.57
Mutation Taster		=98/2	polymorphism (auto)

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: rs2273285; hg19: chr1-12010469; COSMIC: COSV107212593; COSMIC: COSV107212593;