rs61739916

Positions:

• chr19-18786630-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 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

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a region_of_interest Disordered (size 205) in uniprot entity COMP_HUMAN there are 109 pathogenic changes around while only 1 benign (99%) in NM_000095.3
• 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 id is 40987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18786630-T-C is described in Lovd as [Benign]. Variant chr19-18786630-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COMP	NM_000095.3	c.1156A>G	p.Asn386Asp	missense_variant	11/19	ENST00000222271.7	NP_000086.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COMP	ENST00000222271.7	c.1156A>G	p.Asn386Asp	missense_variant	11/19	1	NM_000095.3	ENSP00000222271	P1
COMP	ENST00000542601.6	c.1057A>G	p.Asn353Asp	missense_variant	10/18	1		ENSP00000439156
COMP	ENST00000425807.1	c.997A>G	p.Asn333Asp	missense_variant	10/18	2		ENSP00000403792
COMP	ENST00000612179.1	n.406A>G		non_coding_transcript_exon_variant	1/3	2

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

GnomAD3 exomes AF: 0.0329 AC: 8278 AN: 251324 Hom.: 172 AF XY: 0.0346 AC XY: 4698 AN XY: 135876

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 SAS exome AF: 0.0368

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

Gnomad4 AFR exome AF: 0.00681

Gnomad4 AMR exome AF: 0.0182

Gnomad4 ASJ exome AF: 0.0289

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0367

Gnomad4 FIN exome AF: 0.0303

Gnomad4 NFE exome AF: 0.0517

Gnomad4 OTH exome AF: 0.0438

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

Gnomad4 AFR AF: 0.00939

Gnomad4 AMR AF: 0.0278

Gnomad4 ASJ AF: 0.0366

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0372

Gnomad4 FIN AF: 0.0261

Gnomad4 NFE AF: 0.0487

Gnomad4 OTH AF: 0.0303

Alfa AF: 0.0429 Hom.: 185

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

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome Benign:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Multiple epiphyseal dysplasia type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 23, 2022

- -

Computational scores

Source: dbNSFP v4.3

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;D;D
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Pathogenic	4.2	.;H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.022	D;D;T
Polyphen		1.0	.;D;.
Vest4		0.28
ClinPred		0.041	T
GERP RS		3.4
Varity_R		0.96
gMVP		0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs61739916; hg19: chr19-18897440;