rs12483377

Variant names:

• chr21-45511195-G-A
• rs12483377
• NM_001379500.1:c.3778G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001379500.1(COL18A1):​c.3778G>A​(p.Asp1260Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0783 in 1,592,926 control chromosomes in the GnomAD database, including 5,341 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. D1260Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.066 (370 hom., cov: 31)
  • Exomes 𝑓: 0.080 (4971 hom.)
• Consequence: COL18A1 NM_001379500.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:10
• Conservation: PhyloP100: 6.54
• Publications: 58 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005586356).
• BP6: Variant 21-45511195-G-A is Benign according to our data. Variant chr21-45511195-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 17118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0887 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.3778G>A	p.Asp1260Asn	missense	Exon 41 of 42	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.5023G>A	p.Asp1675Asn	missense	Exon 40 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.4318G>A	p.Asp1440Asn	missense	Exon 40 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.3778G>A	p.Asp1260Asn	missense	Exon 41 of 42	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.4318G>A	p.Asp1440Asn	missense	Exon 40 of 41	ENSP00000347665.5	P39060-1
	SLC19A1	ENST00000567670.5	TSL:1	c.1294-12583C>T		intron	N/A	ENSP00000457278.1	H3BTQ3

Frequencies

GnomAD3 genomes AF: 0.0662 AC: 10055 AN: 151896 Hom.: 370 Cov.: 31

Gnomad AFR AF: 0.0365

Gnomad AMI AF: 0.0604

Gnomad AMR AF: 0.0629

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.0159

Gnomad SAS AF: 0.0462

Gnomad FIN AF: 0.0515

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0906

Gnomad OTH AF: 0.0714

GnomAD2 exomes AF: 0.0656 AC: 14042 AN: 214196 AF XY: 0.0666

Gnomad AFR exome AF: 0.0359

Gnomad AMR exome AF: 0.0403

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.0155

Gnomad FIN exome AF: 0.0565

Gnomad NFE exome AF: 0.0886

Gnomad OTH exome AF: 0.0769

GnomAD4 exome AF: 0.0796 AC: 114648 AN: 1440912 Hom.: 4971 Cov.: 31 AF XY: 0.0791 AC XY: 56558 AN XY: 715102

African (AFR) AF: 0.0336 AC: 1111 AN: 33080

American (AMR) AF: 0.0431 AC: 1826 AN: 42412

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 2602 AN: 25756

East Asian (EAS) AF: 0.0104 AC: 405 AN: 38764

South Asian (SAS) AF: 0.0496 AC: 4124 AN: 83134

European-Finnish (FIN) AF: 0.0540 AC: 2794 AN: 51704

Middle Eastern (MID) AF: 0.0777 AC: 446 AN: 5740

European-Non Finnish (NFE) AF: 0.0880 AC: 96832 AN: 1100758

Other (OTH) AF: 0.0757 AC: 4508 AN: 59564

GnomAD4 genome AF: 0.0661 AC: 10054 AN: 152014 Hom.: 370 Cov.: 31 AF XY: 0.0635 AC XY: 4718 AN XY: 74300

African (AFR) AF: 0.0364 AC: 1512 AN: 41492

American (AMR) AF: 0.0628 AC: 960 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 354 AN: 3472

East Asian (EAS) AF: 0.0157 AC: 81 AN: 5160

South Asian (SAS) AF: 0.0458 AC: 220 AN: 4802

European-Finnish (FIN) AF: 0.0515 AC: 545 AN: 10576

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0906 AC: 6154 AN: 67914

Other (OTH) AF: 0.0706 AC: 149 AN: 2110

Alfa AF: 0.0827 Hom.: 2574

Bravo AF: 0.0650

TwinsUK AF: 0.0968 AC: 359

ALSPAC AF: 0.0939 AC: 362

ESP6500AA AF: 0.0358 AC: 142

ESP6500EA AF: 0.0878 AC: 732

ExAC AF: 0.0586 AC: 7022

Asia WGS AF: 0.0310 AC: 110 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
1	-	2	Knobloch syndrome (3)
-	-	3	not specified (3)
-	-	1	Knobloch syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.42
Sift	Benign	0.057	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.49
MPC		0.38
ClinPred		0.0098	T
GERP RS		5.0
Varity_R		0.59
gMVP		0.67
Mutation Taster		=95/5	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: rs12483377; hg19: chr21-46931109; COSMIC: COSV60587742; COSMIC: COSV60587742;