rs61735029

chr21-45455676-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000355480.10(COL18A1):c.146A>T(p.Gln49Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,613,820 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.012 (29 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (33 hom.)
• Consequence: COL18A1 ENST00000355480.10 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.02

Genes affected

COL18A1 (HGNC:2195): (collagen type XVIII alpha 1 chain) This gene encodes the alpha chain of type XVIII collagen. This collagen is one of the multiplexins, extracellular matrix proteins that contain multiple triple-helix domains (collagenous domains) interrupted by non-collagenous domains. A long isoform of the protein has an N-terminal domain that is homologous to the extracellular part of frizzled receptors. Proteolytic processing at several endogenous cleavage sites in the C-terminal domain results in production of endostatin, a potent antiangiogenic protein that is able to inhibit angiogenesis and tumor growth. Mutations in this gene are associated with Knobloch syndrome. The main features of this syndrome involve retinal abnormalities, so type XVIII collagen may play an important role in retinal structure and in neural tube closure. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003584385).
• BP6: Variant 21-45455676-A-T is Benign according to our data. Variant chr21-45455676-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 445671.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 = 0.0116 (1772/152294) while in subpopulation AFR AF= 0.0405 (1682/41560). AF 95% confidence interval is 0.0389. There are 29 homozygotes in gnomad4. There are 850 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.107-12566A>T		intron_variant		ENST00000651438.1
COL18A1	NM_130444.3	c.146A>T	p.Gln49Leu	missense_variant	1/41
COL18A1	NM_030582.4	c.146A>T	p.Gln49Leu	missense_variant	1/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000355480.10	c.146A>T	p.Gln49Leu	missense_variant	1/41	1
COL18A1	ENST00000651438.1	c.107-12566A>T		intron_variant			NM_001379500.1
COL18A1	ENST00000359759.8	c.146A>T	p.Gln49Leu	missense_variant	1/41	5		P1

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1769 AN: 152176 Hom.: 29 Cov.: 33

Gnomad AFR AF: 0.0405

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00300 AC: 749 AN: 249388 Hom.: 17 AF XY: 0.00222 AC XY: 301 AN XY: 135362

Gnomad AFR exome AF: 0.0420

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000265

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.00127 AC: 1855 AN: 1461526 Hom.: 33 Cov.: 72 AF XY: 0.00112 AC XY: 815 AN XY: 727088

Gnomad4 AFR exome AF: 0.0418

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000139

Gnomad4 OTH exome AF: 0.00288

GnomAD4 genome AF: 0.0116 AC: 1772 AN: 152294 Hom.: 29 Cov.: 33 AF XY: 0.0114 AC XY: 850 AN XY: 74454

Gnomad4 AFR AF: 0.0405

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00354 Hom.: 2

Bravo AF: 0.0130

ESP6500AA AF: 0.0362 AC: 151

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.00377 AC: 457

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 19, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	0.57
Dann	Benign	0.86
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.24	T;T
MetaRNN	Benign	0.0036	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.14
Sift	Benign	0.050	D;D
Sift4G	Benign	0.16	T;T
Polyphen		0.0030	B;B
Vest4		0.13
MVP		0.22
MPC		0.066
ClinPred		0.0027	T
GERP RS		-6.7
Varity_R		0.049
gMVP		0.076

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: rs61735029; hg19: chr21-46875590;