rs150008764

Variant names:

• chr19-18790128-G-A
• rs150008764
• NM_000095.3:c.218-14C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-18790128-G-A
• chr19-18790128-G-C
• chr19-18790128-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000095.3(COMP):​c.218-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,520,822 control chromosomes in the GnomAD database, including 272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (25 hom., cov: 31)
  • Exomes 𝑓: 0.017 (247 hom.)
• Consequence: COMP NM_000095.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.623
• Publications: 2 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=-0.84).
• BP6: Variant 19-18790128-G-A is Benign according to our data. Variant chr19-18790128-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0131 (1996/152016) while in subpopulation NFE AF = 0.0197 (1339/67894). AF 95% confidence interval is 0.0188. There are 25 homozygotes in GnomAd4. There are 998 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1996 AD,Unknown gene.

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.218-14C>T		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.218-14C>T		intron	N/A	ENSP00000222271.2	P49747-1
	COMP	ENST00000542601.6	TSL:1	c.119-14C>T		intron	N/A	ENSP00000439156.2	G3XAP6
	COMP	ENST00000944187.1		c.218-14C>T		intron	N/A	ENSP00000614246.1

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1997 AN: 151898 Hom.: 25 Cov.: 31

Gnomad AFR AF: 0.00363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.00664

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.0189

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0197

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0129 AC: 1580 AN: 122210 AF XY: 0.0130

Gnomad AFR exome AF: 0.00262

Gnomad AMR exome AF: 0.0120

Gnomad ASJ exome AF: 0.00644

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0173

Gnomad NFE exome AF: 0.0204

Gnomad OTH exome AF: 0.0155

GnomAD4 exome AF: 0.0170 AC: 23337 AN: 1368806 Hom.: 247 Cov.: 33 AF XY: 0.0168 AC XY: 11327 AN XY: 673144

African (AFR) AF: 0.00325 AC: 101 AN: 31064

American (AMR) AF: 0.0115 AC: 398 AN: 34566

Ashkenazi Jewish (ASJ) AF: 0.00592 AC: 143 AN: 24146

East Asian (EAS) AF: 0.0000566 AC: 2 AN: 35342

South Asian (SAS) AF: 0.00775 AC: 600 AN: 77402

European-Finnish (FIN) AF: 0.0159 AC: 601 AN: 37682

Middle Eastern (MID) AF: 0.0161 AC: 64 AN: 3982

European-Non Finnish (NFE) AF: 0.0192 AC: 20548 AN: 1067804

Other (OTH) AF: 0.0155 AC: 880 AN: 56818

GnomAD4 genome AF: 0.0131 AC: 1996 AN: 152016 Hom.: 25 Cov.: 31 AF XY: 0.0134 AC XY: 998 AN XY: 74314

African (AFR) AF: 0.00361 AC: 150 AN: 41498

American (AMR) AF: 0.0153 AC: 234 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00664 AC: 23 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4830

European-Finnish (FIN) AF: 0.0189 AC: 200 AN: 10594

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0197 AC: 1339 AN: 67894

Other (OTH) AF: 0.0109 AC: 23 AN: 2112

Alfa AF: 0.00863 Hom.: 1

Bravo AF: 0.0119

Asia WGS AF: 0.00260 AC: 9 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Multiple epiphyseal dysplasia type 1 (1)
-	-	1	Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.6
DANN	Benign	0.93
PhyloP100		-0.62
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: rs150008764; hg19: chr19-18900937;