rs7551175

Variant names:

• chr1-11949899-G-A
• rs7551175
• NM_000302.4:c.295G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-11949899-G-A
• chr1-11949899-G-T

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.295G>A​(p.Ala99Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 1,613,404 control chromosomes in the GnomAD database, including 31,170 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A99A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.26 (7504 hom., cov: 32)
  • Exomes 𝑓: 0.17 (23666 hom.)
• Consequence: PLOD1 NM_000302.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.26
• Publications: 35 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 (MetaRNN=1.0392534E-4).
• BP6: Variant 1-11949899-G-A is Benign according to our data. Variant chr1-11949899-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.535 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.295G>A	p.Ala99Thr	missense	Exon 3 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.436G>A	p.Ala146Thr	missense	Exon 4 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.295G>A	p.Ala99Thr	missense	Exon 3 of 19	ENSP00000196061.4	Q02809-1
	PLOD1	ENST00000854019.1		c.439G>A	p.Ala147Thr	missense	Exon 4 of 20	ENSP00000524078.1
	PLOD1	ENST00000854031.1		c.295G>A	p.Ala99Thr	missense	Exon 3 of 20	ENSP00000524090.1

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39354 AN: 151932 Hom.: 7475 Cov.: 32

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.255

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.231

GnomAD2 exomes AF: 0.181 AC: 45490 AN: 251356 AF XY: 0.176

Gnomad AFR exome AF: 0.550

Gnomad AMR exome AF: 0.0894

Gnomad ASJ exome AF: 0.145

Gnomad EAS exome AF: 0.253

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.153

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.167 AC: 243327 AN: 1461354 Hom.: 23666 Cov.: 34 AF XY: 0.166 AC XY: 120609 AN XY: 727014

African (AFR) AF: 0.546 AC: 18272 AN: 33460

American (AMR) AF: 0.0957 AC: 4280 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3570 AN: 26136

East Asian (EAS) AF: 0.240 AC: 9536 AN: 39690

South Asian (SAS) AF: 0.208 AC: 17900 AN: 86248

European-Finnish (FIN) AF: 0.121 AC: 6450 AN: 53394

Middle Eastern (MID) AF: 0.136 AC: 785 AN: 5764

European-Non Finnish (NFE) AF: 0.154 AC: 170999 AN: 1111556

Other (OTH) AF: 0.191 AC: 11535 AN: 60386

GnomAD4 genome AF: 0.259 AC: 39433 AN: 152050 Hom.: 7504 Cov.: 32 AF XY: 0.255 AC XY: 18932 AN XY: 74334

African (AFR) AF: 0.541 AC: 22409 AN: 41438

American (AMR) AF: 0.142 AC: 2163 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 449 AN: 3472

East Asian (EAS) AF: 0.255 AC: 1316 AN: 5168

South Asian (SAS) AF: 0.215 AC: 1037 AN: 4820

European-Finnish (FIN) AF: 0.114 AC: 1206 AN: 10594

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.150 AC: 10189 AN: 67974

Other (OTH) AF: 0.229 AC: 484 AN: 2110

Alfa AF: 0.191 Hom.: 9169

Bravo AF: 0.271

TwinsUK AF: 0.156 AC: 579

ALSPAC AF: 0.163 AC: 628

ESP6500AA AF: 0.535 AC: 2356

ESP6500EA AF: 0.150 AC: 1293

ExAC AF: 0.193 AC: 23472

Asia WGS AF: 0.260 AC: 902 AN: 3478

EpiCase AF: 0.144

EpiControl AF: 0.150

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	Ehlers-Danlos syndrome, kyphoscoliotic type 1 (3)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.72
DEOGEN2	Benign	0.0095	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.00010	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-2.4	N
PhyloP100		1.3
PrimateAI	Benign	0.42	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.091
MPC		0.20
ClinPred		0.0018	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.017
gMVP		0.45
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: rs7551175; hg19: chr1-12009956; COSMIC: COSV52140857; COSMIC: COSV52140857;