rs377715562

Variant names:

• chr21-45509341-G-A
• rs377715562
• NM_001379500.1:c.3250-15G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-45509341-G-A
• chr21-45509341-G-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001379500.1(COL18A1):​c.3250-15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,543,552 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (18 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.789
• Publications: 0 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 21-45509341-G-A is Benign according to our data. Variant chr21-45509341-G-A is described in ClinVar as Benign. ClinVar VariationId is 261909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	NM_001379500.1	MANE Select	c.3250-15G>A		intron	N/A	NP_001366429.1
	COL18A1	NM_130444.3		c.4495-15G>A		intron	N/A	NP_569711.2
	COL18A1	NM_030582.4		c.3790-15G>A		intron	N/A	NP_085059.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.3250-15G>A		intron	N/A	ENSP00000498485.1
	COL18A1	ENST00000355480.10	TSL:1	c.3790-15G>A		intron	N/A	ENSP00000347665.5
	SLC19A1	ENST00000567670.5	TSL:1	c.1294-10729C>T		intron	N/A	ENSP00000457278.1

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 339 AN: 152122 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00368 AC: 528 AN: 143294 AF XY: 0.00391

Gnomad AFR exome AF: 0.000290

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.0288

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00229

Gnomad OTH exome AF: 0.00715

GnomAD4 exome AF: 0.00196 AC: 2733 AN: 1391312 Hom.: 18 Cov.: 32 AF XY: 0.00210 AC XY: 1440 AN XY: 686970

African (AFR) AF: 0.000570 AC: 18 AN: 31578

American (AMR) AF: 0.00213 AC: 78 AN: 36552

Ashkenazi Jewish (ASJ) AF: 0.0288 AC: 724 AN: 25106

East Asian (EAS) AF: 0.0000558 AC: 2 AN: 35840

South Asian (SAS) AF: 0.00407 AC: 323 AN: 79448

European-Finnish (FIN) AF: 0.0000238 AC: 1 AN: 41950

Middle Eastern (MID) AF: 0.0136 AC: 60 AN: 4398

European-Non Finnish (NFE) AF: 0.00119 AC: 1285 AN: 1078704

Other (OTH) AF: 0.00419 AC: 242 AN: 57736

GnomAD4 genome AF: 0.00223 AC: 339 AN: 152240 Hom.: 2 Cov.: 33 AF XY: 0.00220 AC XY: 164 AN XY: 74438

African (AFR) AF: 0.000506 AC: 21 AN: 41530

American (AMR) AF: 0.00301 AC: 46 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 106 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00187 AC: 127 AN: 67990

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00527 Hom.: 1

Bravo AF: 0.00251

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.4
DANN	Benign	0.63
PhyloP100		-0.79
RBP_binding_hub_radar		0.91
RBP_regulation_power_radar		2.2
Mutation Taster		=100/0	polymorphism

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: rs377715562; hg19: chr21-46929255;