chr1-11963598-C-T

Variant names:

• chr1-11963598-C-T
• rs74949176
• NM_000302.4:c.1164C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001316320.2(PLOD1):​c.1305C>T​(p.Thr435Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000342 in 1,602,802 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T435T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: PLOD1 NM_001316320.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.74
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, PanelApp Australia, G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 1-11963598-C-T is Benign according to our data. Variant chr1-11963598-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 390574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.74 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00162 (246/152262) while in subpopulation AFR AF = 0.00568 (236/41542). AF 95% confidence interval is 0.00509. There are 2 homozygotes in GnomAd4. There are 117 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001316320.2. 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.1164C>T	p.Thr388Thr	synonymous	Exon 11 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.1305C>T	p.Thr435Thr	synonymous	Exon 12 of 20	NP_001303249.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLOD1	ENST00000196061.5	TSL:1 MANE Select	c.1164C>T	p.Thr388Thr	synonymous	Exon 11 of 19	ENSP00000196061.4
	PLOD1	ENST00000854019.1		c.1308C>T	p.Thr436Thr	synonymous	Exon 12 of 20	ENSP00000524078.1
	PLOD1	ENST00000854031.1		c.1251C>T	p.Thr417Thr	synonymous	Exon 12 of 20	ENSP00000524090.1

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 246 AN: 152144 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00570

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000484 AC: 111 AN: 229396 AF XY: 0.000340

Gnomad AFR exome AF: 0.00644

Gnomad AMR exome AF: 0.000315

Gnomad ASJ exome AF: 0.000105

Gnomad EAS exome AF: 0.000176

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000289

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000208 AC: 302 AN: 1450540 Hom.: 1 Cov.: 31 AF XY: 0.000190 AC XY: 137 AN XY: 720348

African (AFR) AF: 0.00676 AC: 226 AN: 33420

American (AMR) AF: 0.000305 AC: 13 AN: 42638

Ashkenazi Jewish (ASJ) AF: 0.0000388 AC: 1 AN: 25778

East Asian (EAS) AF: 0.000229 AC: 9 AN: 39284

South Asian (SAS) AF: 0.000119 AC: 10 AN: 83926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52332

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5752

European-Non Finnish (NFE) AF: 0.0000208 AC: 23 AN: 1107428

Other (OTH) AF: 0.000283 AC: 17 AN: 59982

GnomAD4 genome AF: 0.00162 AC: 246 AN: 152262 Hom.: 2 Cov.: 31 AF XY: 0.00157 AC XY: 117 AN XY: 74444

African (AFR) AF: 0.00568 AC: 236 AN: 41542

American (AMR) AF: 0.000523 AC: 8 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000801 Hom.: 0

Bravo AF: 0.00203

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.012
DANN	Benign	0.70
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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: rs74949176; hg19: chr1-12023655;