NM_000302.4:c.76+264A>G

Variant names:

• chr1-11935119-A-G
• rs1208984
• NM_000302.4:c.76+264A>G

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.76+264A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 152,128 control chromosomes in the GnomAD database, including 14,136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.41 (14136 hom., cov: 33)
• Consequence: PLOD1 NM_000302.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0150
• Publications: 7 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 (BayesDel_noAF=-0.88).
• BP6: Variant 1-11935119-A-G is Benign according to our data. Variant chr1-11935119-A-G is described in ClinVar as Benign. ClinVar VariationId is 683700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.581 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.76+264A>G		intron	N/A	NP_000293.2
	PLOD1	NM_001316320.2		c.76+264A>G		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.76+264A>G		intron	N/A	ENSP00000196061.4	Q02809-1
	PLOD1	ENST00000854019.1		c.76+264A>G		intron	N/A	ENSP00000524078.1
	PLOD1	ENST00000854031.1		c.76+264A>G		intron	N/A	ENSP00000524090.1

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62978 AN: 152012 Hom.: 14110 Cov.: 33

Gnomad AFR AF: 0.586

Gnomad AMI AF: 0.536

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.300

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.386

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

GnomAD4 genome AF: 0.414 AC: 63049 AN: 152128 Hom.: 14136 Cov.: 33 AF XY: 0.406 AC XY: 30218 AN XY: 74376

African (AFR) AF: 0.587 AC: 24357 AN: 41514

American (AMR) AF: 0.280 AC: 4273 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.380 AC: 1318 AN: 3470

East Asian (EAS) AF: 0.200 AC: 1034 AN: 5178

South Asian (SAS) AF: 0.362 AC: 1748 AN: 4824

European-Finnish (FIN) AF: 0.300 AC: 3173 AN: 10584

Middle Eastern (MID) AF: 0.370 AC: 108 AN: 292

European-Non Finnish (NFE) AF: 0.379 AC: 25733 AN: 67970

Other (OTH) AF: 0.386 AC: 817 AN: 2114

Alfa AF: 0.391 Hom.: 23976

Bravo AF: 0.419

Asia WGS AF: 0.316 AC: 1103 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.1
DANN	Benign	0.51
PhyloP100		0.015
PromoterAI		0.041	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1208984; hg19: chr1-11995176;