rs7499

Variant names:

• chr21-45512414-G-A
• rs7499
• NM_001379500.1:c.*16G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-45512414-G-A
• chr21-45512414-G-T

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.*16G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 1,608,724 control chromosomes in the GnomAD database, including 134,572 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13265 hom., cov: 33)
  • Exomes 𝑓: 0.41 (121307 hom.)
• Consequence: COL18A1 NM_001379500.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.08
• Publications: 47 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 (BayesDel_noAF=-0.88).
• BP6: Variant 21-45512414-G-A is Benign according to our data. Variant chr21-45512414-G-A is described in ClinVar as Benign. ClinVar VariationId is 261884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.555 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.*16G>A		3_prime_UTR	Exon 42 of 42	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.*16G>A		3_prime_UTR	Exon 41 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.*16G>A		3_prime_UTR	Exon 41 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.*16G>A		3_prime_UTR	Exon 42 of 42	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.*16G>A		3_prime_UTR	Exon 41 of 41	ENSP00000347665.5	P39060-1
	SLC19A1	ENST00000567670.5	TSL:1	c.1293+13403C>T		intron	N/A	ENSP00000457278.1	H3BTQ3

Frequencies

GnomAD3 genomes AF: 0.416 AC: 63233 AN: 151950 Hom.: 13255 Cov.: 33

Gnomad AFR AF: 0.439

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.572

Gnomad SAS AF: 0.426

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.438

GnomAD2 exomes AF: 0.419 AC: 100466 AN: 239992 AF XY: 0.416

Gnomad AFR exome AF: 0.446

Gnomad AMR exome AF: 0.420

Gnomad ASJ exome AF: 0.383

Gnomad EAS exome AF: 0.570

Gnomad FIN exome AF: 0.404

Gnomad NFE exome AF: 0.396

Gnomad OTH exome AF: 0.429

GnomAD4 exome AF: 0.406 AC: 590934 AN: 1456656 Hom.: 121307 Cov.: 37 AF XY: 0.405 AC XY: 293592 AN XY: 724348

African (AFR) AF: 0.448 AC: 14955 AN: 33414

American (AMR) AF: 0.420 AC: 18572 AN: 44238

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 10048 AN: 26036

East Asian (EAS) AF: 0.601 AC: 23774 AN: 39578

South Asian (SAS) AF: 0.419 AC: 35898 AN: 85728

European-Finnish (FIN) AF: 0.402 AC: 20796 AN: 51758

Middle Eastern (MID) AF: 0.459 AC: 2606 AN: 5678

European-Non Finnish (NFE) AF: 0.396 AC: 439368 AN: 1110016

Other (OTH) AF: 0.414 AC: 24917 AN: 60210

GnomAD4 genome AF: 0.416 AC: 63260 AN: 152068 Hom.: 13265 Cov.: 33 AF XY: 0.420 AC XY: 31179 AN XY: 74322

African (AFR) AF: 0.439 AC: 18213 AN: 41478

American (AMR) AF: 0.403 AC: 6160 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 1315 AN: 3472

East Asian (EAS) AF: 0.573 AC: 2955 AN: 5160

South Asian (SAS) AF: 0.427 AC: 2058 AN: 4822

European-Finnish (FIN) AF: 0.412 AC: 4358 AN: 10576

Middle Eastern (MID) AF: 0.459 AC: 134 AN: 292

European-Non Finnish (NFE) AF: 0.394 AC: 26791 AN: 67950

Other (OTH) AF: 0.436 AC: 922 AN: 2116

Alfa AF: 0.405 Hom.: 30577

Bravo AF: 0.417

Asia WGS AF: 0.486 AC: 1689 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Knobloch syndrome (4)
-	-	2	not provided (2)
-	-	1	Hereditary glaucoma, primary closed-angle (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.17
DANN	Benign	0.80
PhyloP100		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs7499; hg19: chr21-46932328; COSMIC: COSV60589997; COSMIC: COSV60589997;