rs116499541

Variant names:

• chr19-18783046-C-T
• rs116499541
• NM_000095.3:c.2227+8G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-18783046-C-T
• chr19-18783046-C-A
• chr19-18783046-C-G

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.2227+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,612,206 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (49 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (28 hom.)
• Consequence: COMP NM_000095.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001277
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.21
• 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=-0.76).
• BP6: Variant 19-18783046-C-T is Benign according to our data. Variant chr19-18783046-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0135 (2052/152334) while in subpopulation AFR AF = 0.046 (1914/41574). AF 95% confidence interval is 0.0443. There are 49 homozygotes in GnomAd4. There are 984 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2052 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.2227+8G>A		splice_region 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.2227+8G>A		splice_region intron	N/A	ENSP00000222271.2	P49747-1
	COMP	ENST00000542601.6	TSL:1	c.2128+8G>A		splice_region intron	N/A	ENSP00000439156.2	G3XAP6
	COMP	ENST00000944187.1		c.2314+8G>A		splice_region intron	N/A	ENSP00000614246.1

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2043 AN: 152216 Hom.: 49 Cov.: 33

Gnomad AFR AF: 0.0460

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00363 AC: 903 AN: 248908 AF XY: 0.00260

Gnomad AFR exome AF: 0.0494

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000204

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00136 AC: 1985 AN: 1459872 Hom.: 28 Cov.: 32 AF XY: 0.00116 AC XY: 841 AN XY: 726288

African (AFR) AF: 0.0458 AC: 1533 AN: 33480

American (AMR) AF: 0.00219 AC: 98 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51458

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5766

European-Non Finnish (NFE) AF: 0.000155 AC: 172 AN: 1111978

Other (OTH) AF: 0.00268 AC: 162 AN: 60384

GnomAD4 genome AF: 0.0135 AC: 2052 AN: 152334 Hom.: 49 Cov.: 33 AF XY: 0.0132 AC XY: 984 AN XY: 74486

African (AFR) AF: 0.0460 AC: 1914 AN: 41574

American (AMR) AF: 0.00653 AC: 100 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68032

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.00425 Hom.: 4

Bravo AF: 0.0156

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely 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	Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.7
DANN	Benign	0.91
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.0020
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: rs116499541; hg19: chr19-18893856;