21-45507575-A-G

Variant names:

• chr21-45507575-A-G
• rs12483761
• NM_001379500.1:c.3231A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001379500.1(COL18A1):​c.3231A>G​(p.Thr1077Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,611,882 control chromosomes in the GnomAD database, including 13,605 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1533 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12072 hom.)
• Consequence: COL18A1 NM_001379500.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.53
• Publications: 10 publications found

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]

SLC19A1 Gene-Disease associations (from GenCC):

• combined immunodeficiency

  Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia
• immunodeficiency 114, folate-responsive

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• megaloblastic anemia, folate-responsive

  Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 21-45507575-A-G is Benign according to our data. Variant chr21-45507575-A-G is described in ClinVar as Benign. ClinVar VariationId is 261908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379500.1. 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
	COL18A1	NM_001379500.1	MANE Select	c.3231A>G	p.Thr1077Thr	synonymous	Exon 38 of 42	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.4476A>G	p.Thr1492Thr	synonymous	Exon 37 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.3771A>G	p.Thr1257Thr	synonymous	Exon 37 of 41	NP_085059.2	A0AAG2UXZ5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.3231A>G	p.Thr1077Thr	synonymous	Exon 38 of 42	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.3771A>G	p.Thr1257Thr	synonymous	Exon 37 of 41	ENSP00000347665.5	P39060-1
	SLC19A1	ENST00000567670.5	TSL:1	c.1294-8963T>C		intron	N/A	ENSP00000457278.1	H3BTQ3

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21095 AN: 152010 Hom.: 1529 Cov.: 33

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.0169

Gnomad SAS AF: 0.0812

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.147

GnomAD2 exomes AF: 0.125 AC: 30724 AN: 246296 AF XY: 0.122

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.0163

Gnomad FIN exome AF: 0.158

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.126 AC: 183711 AN: 1459754 Hom.: 12072 Cov.: 33 AF XY: 0.125 AC XY: 90455 AN XY: 726162

African (AFR) AF: 0.146 AC: 4874 AN: 33444

American (AMR) AF: 0.182 AC: 8083 AN: 44534

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 3274 AN: 26116

East Asian (EAS) AF: 0.0111 AC: 440 AN: 39690

South Asian (SAS) AF: 0.0880 AC: 7580 AN: 86176

European-Finnish (FIN) AF: 0.161 AC: 8445 AN: 52486

Middle Eastern (MID) AF: 0.115 AC: 657 AN: 5730

European-Non Finnish (NFE) AF: 0.129 AC: 142837 AN: 1111248

Other (OTH) AF: 0.125 AC: 7521 AN: 60330

GnomAD4 genome AF: 0.139 AC: 21112 AN: 152128 Hom.: 1533 Cov.: 33 AF XY: 0.138 AC XY: 10255 AN XY: 74372

African (AFR) AF: 0.150 AC: 6221 AN: 41478

American (AMR) AF: 0.185 AC: 2834 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 446 AN: 3470

East Asian (EAS) AF: 0.0168 AC: 87 AN: 5180

South Asian (SAS) AF: 0.0802 AC: 387 AN: 4826

European-Finnish (FIN) AF: 0.161 AC: 1708 AN: 10604

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.132 AC: 9004 AN: 67962

Other (OTH) AF: 0.146 AC: 309 AN: 2112

Alfa AF: 0.134 Hom.: 1818

Bravo AF: 0.141

Asia WGS AF: 0.0550 AC: 190 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Knobloch syndrome (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.17
DANN	Benign	0.61
PhyloP100		-3.5
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12483761; hg19: chr21-46927489; COSMIC: COSV60587897; COSMIC: COSV60587897;