chr21-45510233-G-A

Variant names:

• chr21-45510233-G-A
• rs201006742
• NM_001379500.1:c.3665G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001379500.1(COL18A1):​c.3665G>A​(p.Arg1222His) variant causes a missense change. The variant allele was found at a frequency of 0.000705 in 1,606,156 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1222G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00059 (1 hom.)
• Consequence: COL18A1 NM_001379500.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 6.53
• Publications: 3 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]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014780968).
• BP6: Variant 21-45510233-G-A is Benign according to our data. Variant chr21-45510233-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 447129.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	NM_001379500.1	MANE Select	c.3665G>A	p.Arg1222His	missense	Exon 40 of 42	NP_001366429.1
	COL18A1	NM_130444.3		c.4910G>A	p.Arg1637His	missense	Exon 39 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.4205G>A	p.Arg1402His	missense	Exon 39 of 41	NP_085059.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.3665G>A	p.Arg1222His	missense	Exon 40 of 42	ENSP00000498485.1
	COL18A1	ENST00000355480.10	TSL:1	c.4205G>A	p.Arg1402His	missense	Exon 39 of 41	ENSP00000347665.5
	SLC19A1	ENST00000567670.5	TSL:1	c.1294-11621C>T		intron	N/A	ENSP00000457278.1

Frequencies

GnomAD3 genomes AF: 0.00182 AC: 277 AN: 152198 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00560

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000654 AC: 149 AN: 227788 AF XY: 0.000541

Gnomad AFR exome AF: 0.00588

Gnomad AMR exome AF: 0.000269

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000563

Gnomad NFE exome AF: 0.000458

Gnomad OTH exome AF: 0.000882

GnomAD4 exome AF: 0.000588 AC: 855 AN: 1453840 Hom.: 1 Cov.: 32 AF XY: 0.000527 AC XY: 381 AN XY: 722852

African (AFR) AF: 0.00580 AC: 193 AN: 33256

American (AMR) AF: 0.000408 AC: 18 AN: 44064

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25982

East Asian (EAS) AF: 0.00 AC: 0 AN: 39242

South Asian (SAS) AF: 0.0000705 AC: 6 AN: 85076

European-Finnish (FIN) AF: 0.000894 AC: 46 AN: 51440

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.000489 AC: 542 AN: 1109014

Other (OTH) AF: 0.000800 AC: 48 AN: 60006

GnomAD4 genome AF: 0.00183 AC: 278 AN: 152316 Hom.: 0 Cov.: 34 AF XY: 0.00162 AC XY: 121 AN XY: 74478

African (AFR) AF: 0.00561 AC: 233 AN: 41562

American (AMR) AF: 0.000979 AC: 15 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68024

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000909 Hom.: 1

Bravo AF: 0.00223

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00343 AC: 14

ESP6500EA AF: 0.000241 AC: 2

ExAC AF: 0.000827 AC: 99

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	COL18A1-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	0.0055	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		6.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.60
MVP		0.71
MPC		0.45
ClinPred		0.061	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.57
gMVP		0.76
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201006742; hg19: chr21-46930147; COSMIC: COSV100229359; COSMIC: COSV100229359;