rs552712043

Variant names:

• chr1-11934722-G-A
• rs552712043
• NM_000302.4:c.-58G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-11934722-G-A
• chr1-11934722-G-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_000302.4(PLOD1):​c.-58G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,508,574 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: PLOD1 NM_000302.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.54
• 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: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000131 (20/152328) while in subpopulation SAS AF = 0.00373 (18/4832). AF 95% confidence interval is 0.00241. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 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.-58G>A		5_prime_UTR	Exon 1 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.-58G>A		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.-58G>A		5_prime_UTR	Exon 1 of 19	ENSP00000196061.4	Q02809-1
	PLOD1	ENST00000854019.1		c.-58G>A		5_prime_UTR	Exon 1 of 20	ENSP00000524078.1
	PLOD1	ENST00000960558.1		c.-58G>A		5_prime_UTR	Exon 1 of 19	ENSP00000630617.1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000232 AC: 314 AN: 1356246 Hom.: 2 Cov.: 31 AF XY: 0.000300 AC XY: 201 AN XY: 669058

African (AFR) AF: 0.0000726 AC: 2 AN: 27558

American (AMR) AF: 0.00 AC: 0 AN: 32888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24058

East Asian (EAS) AF: 0.00 AC: 0 AN: 31964

South Asian (SAS) AF: 0.00374 AC: 285 AN: 76132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4088

European-Non Finnish (NFE) AF: 9.36e-7 AC: 1 AN: 1068214

Other (OTH) AF: 0.000460 AC: 26 AN: 56544

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74482

African (AFR) AF: 0.0000240 AC: 1 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15308

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

Asia WGS AF: 0.00289 AC: 10 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Ehlers-Danlos syndrome, kyphoscoliotic type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Uncertain	0.98
PhyloP100		1.5
PromoterAI		-0.075	Neutral

Splicing

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

Other links and lift over

dbSNP: rs552712043; hg19: chr1-11994779;