chr1-11974748-T-C

Variant names:

• chr1-11974748-T-C
• rs879690
• NM_000302.4:c.2124T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000302.4(PLOD1):​c.2124T>C​(p.His708His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,613,982 control chromosomes in the GnomAD database, including 870 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (392 hom., cov: 31)
  • Exomes 𝑓: 0.010 (478 hom.)
• Consequence: PLOD1 NM_000302.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.480
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 1-11974748-T-C is Benign according to our data. Variant chr1-11974748-T-C is described in ClinVar as Benign. ClinVar VariationId is 263886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.48 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 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.2124T>C	p.His708His	synonymous	Exon 19 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.2265T>C	p.His755His	synonymous	Exon 20 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.2124T>C	p.His708His	synonymous	Exon 19 of 19	ENSP00000196061.4	Q02809-1
	PLOD1	ENST00000854019.1		c.2268T>C	p.His756His	synonymous	Exon 20 of 20	ENSP00000524078.1
	PLOD1	ENST00000854031.1		c.2211T>C	p.His737His	synonymous	Exon 20 of 20	ENSP00000524090.1

Frequencies

GnomAD3 genomes AF: 0.0434 AC: 6604 AN: 152104 Hom.: 391 Cov.: 31

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0412

Gnomad SAS AF: 0.0302

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00446

Gnomad OTH AF: 0.0320

GnomAD2 exomes AF: 0.0201 AC: 5054 AN: 251340 AF XY: 0.0184

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.0430

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00404

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.0100 AC: 14628 AN: 1461760 Hom.: 478 Cov.: 31 AF XY: 0.0102 AC XY: 7381 AN XY: 727186

African (AFR) AF: 0.145 AC: 4858 AN: 33462

American (AMR) AF: 0.0110 AC: 494 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 32 AN: 26136

East Asian (EAS) AF: 0.0345 AC: 1369 AN: 39700

South Asian (SAS) AF: 0.0303 AC: 2617 AN: 86258

European-Finnish (FIN) AF: 0.000637 AC: 34 AN: 53390

Middle Eastern (MID) AF: 0.0279 AC: 161 AN: 5768

European-Non Finnish (NFE) AF: 0.00364 AC: 4043 AN: 1111934

Other (OTH) AF: 0.0169 AC: 1020 AN: 60388

GnomAD4 genome AF: 0.0436 AC: 6631 AN: 152222 Hom.: 392 Cov.: 31 AF XY: 0.0421 AC XY: 3130 AN XY: 74424

African (AFR) AF: 0.135 AC: 5615 AN: 41510

American (AMR) AF: 0.0176 AC: 269 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.0413 AC: 214 AN: 5186

South Asian (SAS) AF: 0.0304 AC: 147 AN: 4832

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00446 AC: 303 AN: 68000

Other (OTH) AF: 0.0345 AC: 73 AN: 2114

Alfa AF: 0.0159 Hom.: 165

Bravo AF: 0.0495

Asia WGS AF: 0.0440 AC: 154 AN: 3478

EpiCase AF: 0.00502

EpiControl AF: 0.00504

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Ehlers-Danlos syndrome, kyphoscoliotic type 1 (3)
-	-	2	not provided (2)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.1
DANN	Benign	0.53
PhyloP100		-0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs879690; hg19: chr1-12034805;