21-45504469-C-T

Variant names:

• chr21-45504469-C-T
• rs11544970
• NM_001379500.1:c.2781C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001379500.1(COL18A1):​c.2781C>T​(p.Pro927Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,607,824 control chromosomes in the GnomAD database, including 640 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P927P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.024 (53 hom., cov: 33)
  • Exomes 𝑓: 0.025 (587 hom.)
• Consequence: COL18A1 NM_001379500.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.14
• Publications: 12 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=-0.79).
• BP6: Variant 21-45504469-C-T is Benign according to our data. Variant chr21-45504469-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.14 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0237 (3586/151046) while in subpopulation SAS AF = 0.0398 (190/4778). AF 95% confidence interval is 0.0351. There are 53 homozygotes in GnomAd4. There are 1832 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 53 AD,AR gene

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.2781C>T	p.Pro927Pro	synonymous	Exon 34 of 42	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.4026C>T	p.Pro1342Pro	synonymous	Exon 33 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.3321C>T	p.Pro1107Pro	synonymous	Exon 33 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.2781C>T	p.Pro927Pro	synonymous	Exon 34 of 42	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.3321C>T	p.Pro1107Pro	synonymous	Exon 33 of 41	ENSP00000347665.5	P39060-1
	SLC19A1	ENST00000567670.5	TSL:1	c.1294-5857G>A		intron	N/A	ENSP00000457278.1	H3BTQ3

Frequencies

GnomAD3 genomes AF: 0.0237 AC: 3582 AN: 150928 Hom.: 52 Cov.: 33

Gnomad AFR AF: 0.00837

Gnomad AMI AF: 0.0419

Gnomad AMR AF: 0.0328

Gnomad ASJ AF: 0.0531

Gnomad EAS AF: 0.0361

Gnomad SAS AF: 0.0404

Gnomad FIN AF: 0.0298

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0259

Gnomad OTH AF: 0.0328

GnomAD2 exomes AF: 0.0291 AC: 6877 AN: 236534 AF XY: 0.0307

Gnomad AFR exome AF: 0.00922

Gnomad AMR exome AF: 0.0249

Gnomad ASJ exome AF: 0.0573

Gnomad EAS exome AF: 0.0312

Gnomad FIN exome AF: 0.0286

Gnomad NFE exome AF: 0.0257

Gnomad OTH exome AF: 0.0349

GnomAD4 exome AF: 0.0255 AC: 37131 AN: 1456778 Hom.: 587 Cov.: 32 AF XY: 0.0264 AC XY: 19100 AN XY: 724694

African (AFR) AF: 0.00859 AC: 287 AN: 33398

American (AMR) AF: 0.0266 AC: 1188 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.0566 AC: 1476 AN: 26062

East Asian (EAS) AF: 0.0307 AC: 1216 AN: 39662

South Asian (SAS) AF: 0.0428 AC: 3684 AN: 86084

European-Finnish (FIN) AF: 0.0263 AC: 1364 AN: 51810

Middle Eastern (MID) AF: 0.0362 AC: 193 AN: 5330

European-Non Finnish (NFE) AF: 0.0234 AC: 26018 AN: 1109718

Other (OTH) AF: 0.0284 AC: 1705 AN: 60078

GnomAD4 genome AF: 0.0237 AC: 3586 AN: 151046 Hom.: 53 Cov.: 33 AF XY: 0.0248 AC XY: 1832 AN XY: 73806

African (AFR) AF: 0.00837 AC: 344 AN: 41100

American (AMR) AF: 0.0327 AC: 496 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.0531 AC: 184 AN: 3468

East Asian (EAS) AF: 0.0364 AC: 183 AN: 5034

South Asian (SAS) AF: 0.0398 AC: 190 AN: 4778

European-Finnish (FIN) AF: 0.0298 AC: 313 AN: 10504

Middle Eastern (MID) AF: 0.0377 AC: 11 AN: 292

European-Non Finnish (NFE) AF: 0.0259 AC: 1753 AN: 67692

Other (OTH) AF: 0.0353 AC: 74 AN: 2096

Alfa AF: 0.0227 Hom.: 14

Bravo AF: 0.0227

Asia WGS AF: 0.0300 AC: 103 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Knobloch syndrome (3)
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.13
DANN	Benign	0.81
PhyloP100		-4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs11544970; hg19: chr21-46924383; COSMIC: COSV60591302; COSMIC: COSV60591302;