chr1-11965296-T-C

Variant names:

• chr1-11965296-T-C
• rs2273291
• NM_000302.4:c.1471-184T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000302.4(PLOD1):​c.1471-184T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.578 in 151,858 control chromosomes in the GnomAD database, including 27,365 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.58 (27365 hom., cov: 30)
• Consequence: PLOD1 NM_000302.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.03
• Publications: 11 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 1-11965296-T-C is Benign according to our data. Variant chr1-11965296-T-C is described in ClinVar as Benign. ClinVar VariationId is 1263662.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.801 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.1471-184T>C		intron	N/A	NP_000293.2
	PLOD1	NM_001316320.2		c.1612-184T>C		intron	N/A	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.1471-184T>C		intron	N/A	ENSP00000196061.4	Q02809-1
	PLOD1	ENST00000854019.1		c.1615-184T>C		intron	N/A	ENSP00000524078.1
	PLOD1	ENST00000854031.1		c.1558-184T>C		intron	N/A	ENSP00000524090.1

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87623 AN: 151740 Hom.: 27325 Cov.: 30

Gnomad AFR AF: 0.808

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.465

Gnomad ASJ AF: 0.334

Gnomad EAS AF: 0.682

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.567

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.540

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.578 AC: 87727 AN: 151858 Hom.: 27365 Cov.: 30 AF XY: 0.580 AC XY: 43049 AN XY: 74212

African (AFR) AF: 0.808 AC: 33474 AN: 41410

American (AMR) AF: 0.465 AC: 7103 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 1157 AN: 3462

East Asian (EAS) AF: 0.682 AC: 3520 AN: 5162

South Asian (SAS) AF: 0.657 AC: 3153 AN: 4796

European-Finnish (FIN) AF: 0.567 AC: 5977 AN: 10534

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.469 AC: 31844 AN: 67920

Other (OTH) AF: 0.541 AC: 1137 AN: 2100

Alfa AF: 0.511 Hom.: 47635

Bravo AF: 0.575

Asia WGS AF: 0.695 AC: 2415 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.56
DANN	Benign	0.50
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2273291; hg19: chr1-12025353;