NM_000095.3:c.511G>A

Variant names:

• chr19-18789177-C-T
• rs115338183
• NM_000095.3:c.511G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000095.3(COMP):​c.511G>A​(p.Ala171Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00309 in 1,579,168 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (64 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (62 hom.)
• Consequence: COMP NM_000095.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 6.01
• Publications: 5 publications found

Genes affected

COMP (HGNC:2227): (cartilage oligomeric matrix protein) The protein encoded by this gene is a noncollagenous extracellular matrix (ECM) protein. It consists of five identical glycoprotein subunits, each with EGF-like and calcium-binding (thrombospondin-like) domains. Oligomerization results from formation of a five-stranded coiled coil and disulfides. Binding to other ECM proteins such as collagen appears to depend on divalent cations. Contraction or expansion of a 5 aa aspartate repeat and other mutations can cause pseudochondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). [provided by RefSeq, Jul 2016]

COMP Gene-Disease associations (from GenCC):

• COMP-related skeletal dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• multiple epiphyseal dysplasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pseudoachondroplasia

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Illumina, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• multiple epiphyseal dysplasia type 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 127 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.78 (below the threshold of 3.09). Trascript score misZ: 1.5018 (below the threshold of 3.09). GenCC associations: The gene is linked to pseudoachondroplasia, multiple epiphyseal dysplasia type 1, multiple epiphyseal dysplasia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.00695318).
• BP6: Variant 19-18789177-C-T is Benign according to our data. Variant chr19-18789177-C-T is described in ClinVar as Benign. ClinVar VariationId is 197627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0567 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000095.3. 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
	COMP	NM_000095.3	MANE Select	c.511G>A	p.Ala171Thr	missense	Exon 5 of 19	NP_000086.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMP	ENST00000222271.7	TSL:1 MANE Select	c.511G>A	p.Ala171Thr	missense	Exon 5 of 19	ENSP00000222271.2	P49747-1
	COMP	ENST00000542601.6	TSL:1	c.412G>A	p.Ala138Thr	missense	Exon 4 of 18	ENSP00000439156.2	G3XAP6
	COMP	ENST00000944187.1		c.511G>A	p.Ala171Thr	missense	Exon 5 of 20	ENSP00000614246.1

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2582 AN: 152204 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.0585

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00805

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00463 AC: 974 AN: 210202 AF XY: 0.00337

Gnomad AFR exome AF: 0.0619

Gnomad AMR exome AF: 0.00294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000624

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000113

Gnomad OTH exome AF: 0.00142

GnomAD4 exome AF: 0.00160 AC: 2290 AN: 1426846 Hom.: 62 Cov.: 32 AF XY: 0.00148 AC XY: 1052 AN XY: 709182

African (AFR) AF: 0.0574 AC: 1817 AN: 31628

American (AMR) AF: 0.00339 AC: 125 AN: 36880

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23710

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39130

South Asian (SAS) AF: 0.0000621 AC: 5 AN: 80566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51280

Middle Eastern (MID) AF: 0.00485 AC: 27 AN: 5570

European-Non Finnish (NFE) AF: 0.0000919 AC: 101 AN: 1099284

Other (OTH) AF: 0.00364 AC: 214 AN: 58798

GnomAD4 genome AF: 0.0170 AC: 2595 AN: 152322 Hom.: 64 Cov.: 32 AF XY: 0.0164 AC XY: 1220 AN XY: 74484

African (AFR) AF: 0.0586 AC: 2437 AN: 41568

American (AMR) AF: 0.00797 AC: 122 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

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

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68030

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

Alfa AF: 0.00348 Hom.: 26

Bravo AF: 0.0192

ESP6500AA AF: 0.0582 AC: 255

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00552 AC: 668

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Connective tissue disorder (1)
-	-	1	Multiple epiphyseal dysplasia type 1 (1)
-	-	1	Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome (1)
-	-	1	Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome;C1838280:Multiple epiphyseal dysplasia type 1;C5436916:Carpal tunnel syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.60
Sift	Benign	0.035	D
Sift4G	Benign	0.084	T
Polyphen		1.0	D
Vest4		0.60
MVP		0.79
ClinPred		0.039	T
GERP RS		3.0
Varity_R		0.55
gMVP		0.60
Mutation Taster		=75/25	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: rs115338183; hg19: chr19-18899986;