19-18790809-C-G

Variant names:

• chr19-18790809-C-G
• rs35359254
• NM_000095.3:c.165+41G>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.165+41G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,558,104 control chromosomes in the GnomAD database, including 9,944 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2321 hom., cov: 32)
  • Exomes 𝑓: 0.096 (7623 hom.)
• Consequence: COMP NM_000095.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.590
• Publications: 7 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=-0.79).
• BP6: Variant 19-18790809-C-G is Benign according to our data. Variant chr19-18790809-C-G is described in ClinVar as Benign. ClinVar VariationId is 255118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.286 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.165+41G>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.165+41G>C		intron	N/A	ENSP00000222271.2	P49747-1
	COMP	ENST00000542601.6	TSL:1	c.66+41G>C		intron	N/A	ENSP00000439156.2	G3XAP6
	COMP	ENST00000944187.1		c.165+41G>C		intron	N/A	ENSP00000614246.1

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22223 AN: 152086 Hom.: 2310 Cov.: 32

Gnomad AFR AF: 0.290

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0857

Gnomad ASJ AF: 0.0773

Gnomad EAS AF: 0.00559

Gnomad SAS AF: 0.0244

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0991

Gnomad OTH AF: 0.116

GnomAD2 exomes AF: 0.0849 AC: 13525 AN: 159334 AF XY: 0.0809

Gnomad AFR exome AF: 0.299

Gnomad AMR exome AF: 0.0481

Gnomad ASJ exome AF: 0.0824

Gnomad EAS exome AF: 0.00546

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.0803

GnomAD4 exome AF: 0.0958 AC: 134656 AN: 1405900 Hom.: 7623 Cov.: 34 AF XY: 0.0930 AC XY: 64739 AN XY: 695836

African (AFR) AF: 0.306 AC: 9816 AN: 32096

American (AMR) AF: 0.0518 AC: 1906 AN: 36816

Ashkenazi Jewish (ASJ) AF: 0.0843 AC: 2140 AN: 25378

East Asian (EAS) AF: 0.00865 AC: 316 AN: 36550

South Asian (SAS) AF: 0.0246 AC: 2017 AN: 81850

European-Finnish (FIN) AF: 0.134 AC: 5566 AN: 41452

Middle Eastern (MID) AF: 0.0678 AC: 387 AN: 5712

European-Non Finnish (NFE) AF: 0.0984 AC: 107036 AN: 1087498

Other (OTH) AF: 0.0935 AC: 5472 AN: 58548

GnomAD4 genome AF: 0.146 AC: 22267 AN: 152204 Hom.: 2321 Cov.: 32 AF XY: 0.142 AC XY: 10604 AN XY: 74422

African (AFR) AF: 0.290 AC: 12034 AN: 41502

American (AMR) AF: 0.0855 AC: 1308 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0773 AC: 268 AN: 3468

East Asian (EAS) AF: 0.00561 AC: 29 AN: 5172

South Asian (SAS) AF: 0.0244 AC: 118 AN: 4828

European-Finnish (FIN) AF: 0.135 AC: 1432 AN: 10612

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0991 AC: 6740 AN: 68000

Other (OTH) AF: 0.114 AC: 242 AN: 2114

Alfa AF: 0.113 Hom.: 230

Bravo AF: 0.150

Asia WGS AF: 0.0420 AC: 145 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.7
DANN	Benign	0.73
PhyloP100		0.59
PromoterAI		-0.036	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35359254; hg19: chr19-18901618;