rs61739916

Variant names:

• chr19-18786630-T-C
• rs61739916
• NM_000095.3:c.1156A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000095.3(COMP):​c.1156A>G​(p.Asn386Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0445 in 1,613,698 control chromosomes in the GnomAD database, including 1,810 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (104 hom., cov: 31)
  • Exomes 𝑓: 0.046 (1706 hom.)
• Consequence: COMP NM_000095.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 7.88
• Publications: 26 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):

• multiple epiphyseal dysplasia

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

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

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

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000095.3
• 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=0.014269739).
• BP6: Variant 19-18786630-T-C is Benign according to our data. Variant chr19-18786630-T-C is described in ClinVar as Benign. ClinVar VariationId is 40987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0514 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.1156A>G	p.Asn386Asp	missense	Exon 11 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.1156A>G	p.Asn386Asp	missense	Exon 11 of 19	ENSP00000222271.2
	COMP	ENST00000542601.6	TSL:1	c.1057A>G	p.Asn353Asp	missense	Exon 10 of 18	ENSP00000439156.2
	COMP	ENST00000944187.1		c.1156A>G	p.Asn386Asp	missense	Exon 11 of 20	ENSP00000614246.1

Frequencies

GnomAD3 genomes AF: 0.0315 AC: 4794 AN: 152076 Hom.: 104 Cov.: 31

Gnomad AFR AF: 0.00942

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0279

Gnomad ASJ AF: 0.0366

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0372

Gnomad FIN AF: 0.0261

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0488

Gnomad OTH AF: 0.0307

GnomAD2 exomes AF: 0.0329 AC: 8278 AN: 251324 AF XY: 0.0346

Gnomad AFR exome AF: 0.00893

Gnomad AMR exome AF: 0.0169

Gnomad ASJ exome AF: 0.0310

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0294

Gnomad NFE exome AF: 0.0462

Gnomad OTH exome AF: 0.0352

GnomAD4 exome AF: 0.0458 AC: 66940 AN: 1461504 Hom.: 1706 Cov.: 33 AF XY: 0.0457 AC XY: 33217 AN XY: 727092

African (AFR) AF: 0.00681 AC: 228 AN: 33480

American (AMR) AF: 0.0182 AC: 815 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0289 AC: 755 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.0367 AC: 3161 AN: 86248

European-Finnish (FIN) AF: 0.0303 AC: 1618 AN: 53400

Middle Eastern (MID) AF: 0.0329 AC: 190 AN: 5768

European-Non Finnish (NFE) AF: 0.0517 AC: 57527 AN: 1111670

Other (OTH) AF: 0.0438 AC: 2643 AN: 60388

GnomAD4 genome AF: 0.0315 AC: 4789 AN: 152194 Hom.: 104 Cov.: 31 AF XY: 0.0299 AC XY: 2225 AN XY: 74416

African (AFR) AF: 0.00939 AC: 390 AN: 41538

American (AMR) AF: 0.0278 AC: 425 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0366 AC: 127 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0372 AC: 179 AN: 4814

European-Finnish (FIN) AF: 0.0261 AC: 277 AN: 10616

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0487 AC: 3311 AN: 67984

Other (OTH) AF: 0.0303 AC: 64 AN: 2110

Alfa AF: 0.0421 Hom.: 433

Bravo AF: 0.0305

TwinsUK AF: 0.0520 AC: 193

ALSPAC AF: 0.0576 AC: 222

ESP6500AA AF: 0.0136 AC: 60

ESP6500EA AF: 0.0473 AC: 407

ExAC AF: 0.0338 AC: 4099

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.0443

EpiControl AF: 0.0458

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Connective tissue disorder (1)
-	-	1	Multiple epiphyseal dysplasia type 1 (1)
-	-	1	not specified (1)
-	-	1	Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		7.9
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.022	D
Polyphen		1.0	D
Vest4		0.28
ClinPred		0.041	T
GERP RS		3.4
Varity_R		0.96
gMVP		0.88
Mutation Taster		=89/11	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: rs61739916; hg19: chr19-18897440; COSMIC: COSV107292375;