rs1204442973

Variant names:

• chr1-11934751-GT-G
• rs1204442973
• NM_000302.4:c.-28delT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_000302.4(PLOD1):​c.-28delT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 1,522,540 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: PLOD1 NM_000302.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.513
• 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: Genomics England PanelApp, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 1-11934751-GT-G is Benign according to our data. Variant chr1-11934751-GT-G is described in ClinVar as Likely_benign. ClinVar VariationId is 511895.Status of the report is criteria_provided_single_submitter, 1 stars.

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.-28delT		5_prime_UTR	Exon 1 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.-28delT		5_prime_UTR	Exon 1 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.-28delT		5_prime_UTR	Exon 1 of 19	ENSP00000196061.4	Q02809-1
	PLOD1	ENST00000854019.1		c.-28delT		5_prime_UTR	Exon 1 of 20	ENSP00000524078.1
	PLOD1	ENST00000854031.1		c.-28delT		5_prime_UTR	Exon 1 of 20	ENSP00000524090.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000853 AC: 1 AN: 117180 AF XY: 0.0000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000227

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000263 AC: 36 AN: 1370328 Hom.: 0 Cov.: 31 AF XY: 0.0000251 AC XY: 17 AN XY: 676186

African (AFR) AF: 0.00 AC: 0 AN: 28622

American (AMR) AF: 0.00 AC: 0 AN: 34554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24550

East Asian (EAS) AF: 0.00 AC: 0 AN: 33442

South Asian (SAS) AF: 0.00 AC: 0 AN: 77262

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4322

European-Non Finnish (NFE) AF: 0.0000335 AC: 36 AN: 1073320

Other (OTH) AF: 0.00 AC: 0 AN: 57164

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74360

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68026

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000000000768718), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.51

Splicing

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

Other links and lift over

dbSNP: rs1204442973; hg19: chr1-11994808;