rs144147445

chr21-45510178-G-Achr21-45510178-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001379500.1(COL18A1):c.3610G>A(p.Ala1204Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 1,597,036 control chromosomes in the GnomAD database, including 248 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1204G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (18 hom., cov: 34)
  • Exomes 𝑓: 0.016 (230 hom.)
• Consequence: COL18A1 NM_001379500.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 9.68

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]

SLC19A1 (HGNC:10937): (solute carrier family 19 member 1) The membrane protein encoded by this gene is a transporter of folate and is involved in the regulation of intracellular concentrations of folate. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 21-45510178-G-A is Benign according to our data. Variant chr21-45510178-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 261914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45510178-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0101 (1539/152288) while in subpopulation SAS AF= 0.0209 (101/4826). AF 95% confidence interval is 0.0176. There are 18 homozygotes in gnomad4. There are 701 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.3610G>A	p.Ala1204Thr	missense_variant	40/42	ENST00000651438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1	c.3610G>A	p.Ala1204Thr	missense_variant	40/42		NM_001379500.1

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1541 AN: 152170 Hom.: 18 Cov.: 34

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.00782

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0157

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0127 AC: 2670 AN: 209828 Hom.: 22 AF XY: 0.0143 AC XY: 1662 AN XY: 115988

Gnomad AFR exome AF: 0.00290

Gnomad AMR exome AF: 0.00485

Gnomad ASJ exome AF: 0.0184

Gnomad EAS exome AF: 0.000254

Gnomad SAS exome AF: 0.0234

Gnomad FIN exome AF: 0.00604

Gnomad NFE exome AF: 0.0164

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.0164 AC: 23693 AN: 1444748 Hom.: 230 Cov.: 32 AF XY: 0.0167 AC XY: 12018 AN XY: 717598

Gnomad4 AFR exome AF: 0.00276

Gnomad4 AMR exome AF: 0.00525

Gnomad4 ASJ exome AF: 0.0194

Gnomad4 EAS exome AF: 0.000235

Gnomad4 SAS exome AF: 0.0228

Gnomad4 FIN exome AF: 0.00629

Gnomad4 NFE exome AF: 0.0177

Gnomad4 OTH exome AF: 0.0152

GnomAD4 genome AF: 0.0101 AC: 1539 AN: 152288 Hom.: 18 Cov.: 34 AF XY: 0.00941 AC XY: 701 AN XY: 74462

Gnomad4 AFR AF: 0.00318

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0209

Gnomad4 FIN AF: 0.00782

Gnomad4 NFE AF: 0.0157

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0162 Hom.: 15

Bravo AF: 0.00926

TwinsUK AF: 0.0146 AC: 54

ALSPAC AF: 0.0166 AC: 64

ESP6500AA AF: 0.00330 AC: 13

ESP6500EA AF: 0.0144 AC: 118

ExAC AF: 0.0123 AC: 1463

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	COL18A1: BS1, BS2; SLC19A1: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 27, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.080
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D
MetaRNN	Benign	0.018	T;T;T;T
MetaSVM	Uncertain	0.090	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.4	D;D;D;D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;T;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.68
MPC		0.40
ClinPred		0.065	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.69
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: 24

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs144147445; hg19: chr21-46930092;