rs28494505

Variant names:

• chr19-18783001-A-G
• rs28494505
• NM_000095.3:c.2228-40T>C

Your query was ambiguous. Multiple possible variants found:

• chr19-18783001-A-G
• chr19-18783001-A-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000095.3(COMP):​c.2228-40T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 1,611,948 control chromosomes in the GnomAD database, including 24,206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4092 hom., cov: 33)
  • Exomes 𝑓: 0.16 (20114 hom.)
• Consequence: COMP NM_000095.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.15
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 19-18783001-A-G is Benign according to our data. Variant chr19-18783001-A-G is described in ClinVar as Benign. ClinVar VariationId is 255123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.353 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.2228-40T>C		intron	N/A	NP_000086.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMP	ENST00000222271.7	TSL:1 MANE Select	c.2228-40T>C		intron	N/A	ENSP00000222271.2	P49747-1
	COMP	ENST00000542601.6	TSL:1	c.2129-40T>C		intron	N/A	ENSP00000439156.2	G3XAP6
	COMP	ENST00000944187.1		c.2315-40T>C		intron	N/A	ENSP00000614246.1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32253 AN: 152080 Hom.: 4074 Cov.: 33

Gnomad AFR AF: 0.357

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.0982

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.212

GnomAD2 exomes AF: 0.166 AC: 41203 AN: 248552 AF XY: 0.164

Gnomad AFR exome AF: 0.362

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.215

Gnomad EAS exome AF: 0.188

Gnomad FIN exome AF: 0.0998

Gnomad NFE exome AF: 0.155

Gnomad OTH exome AF: 0.158

GnomAD4 exome AF: 0.161 AC: 235199 AN: 1459748 Hom.: 20114 Cov.: 33 AF XY: 0.162 AC XY: 117707 AN XY: 726308

African (AFR) AF: 0.371 AC: 12429 AN: 33478

American (AMR) AF: 0.121 AC: 5396 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 5504 AN: 26130

East Asian (EAS) AF: 0.172 AC: 6838 AN: 39694

South Asian (SAS) AF: 0.177 AC: 15280 AN: 86254

European-Finnish (FIN) AF: 0.100 AC: 5138 AN: 51402

Middle Eastern (MID) AF: 0.183 AC: 1048 AN: 5740

European-Non Finnish (NFE) AF: 0.156 AC: 173106 AN: 1111952

Other (OTH) AF: 0.173 AC: 10460 AN: 60380

GnomAD4 genome AF: 0.212 AC: 32316 AN: 152200 Hom.: 4092 Cov.: 33 AF XY: 0.208 AC XY: 15463 AN XY: 74420

African (AFR) AF: 0.357 AC: 14838 AN: 41506

American (AMR) AF: 0.161 AC: 2466 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 777 AN: 3468

East Asian (EAS) AF: 0.186 AC: 963 AN: 5164

South Asian (SAS) AF: 0.185 AC: 895 AN: 4828

European-Finnish (FIN) AF: 0.0982 AC: 1044 AN: 10628

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10683 AN: 67988

Other (OTH) AF: 0.210 AC: 444 AN: 2114

Alfa AF: 0.128 Hom.: 341

Bravo AF: 0.224

Asia WGS AF: 0.208 AC: 722 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.090
DANN	Benign	0.28
PhyloP100		-1.1
Mutation Taster		=100/0	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: rs28494505; hg19: chr19-18893811; COSMIC: COSV55875173; COSMIC: COSV55875173;