rs1050351

Variant names:

• chr21-45509553-G-A
• rs1050351
• NM_001379500.1:c.3447G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-45509553-G-A
• chr21-45509553-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001379500.1(COL18A1):​c.3447G>A​(p.Ala1149Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 1,532,002 control chromosomes in the GnomAD database, including 138,426 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (14519 hom., cov: 32)
  • Exomes 𝑓: 0.42 (123907 hom.)
• Consequence: COL18A1 NM_001379500.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -6.17
• Publications: 23 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 (REVEL=0.005).
• BP6: Variant 21-45509553-G-A is Benign according to our data. Variant chr21-45509553-G-A is described in ClinVar as Benign. ClinVar VariationId is 261910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.17 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.542 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.3447G>A	p.Ala1149Ala	synonymous	Exon 39 of 42	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.4692G>A	p.Ala1564Ala	synonymous	Exon 38 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.3987G>A	p.Ala1329Ala	synonymous	Exon 38 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.3447G>A	p.Ala1149Ala	synonymous	Exon 39 of 42	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.3987G>A	p.Ala1329Ala	synonymous	Exon 38 of 41	ENSP00000347665.5	P39060-1
	SLC19A1	ENST00000567670.5	TSL:1	c.1294-10941C>T		intron	N/A	ENSP00000457278.1	H3BTQ3

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66217 AN: 151698 Hom.: 14513 Cov.: 32

Gnomad AFR AF: 0.458

Gnomad AMI AF: 0.375

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.384

Gnomad EAS AF: 0.559

Gnomad SAS AF: 0.478

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.404

Gnomad OTH AF: 0.450

GnomAD2 exomes AF: 0.459 AC: 63247 AN: 137678 AF XY: 0.455

Gnomad AFR exome AF: 0.472

Gnomad AMR exome AF: 0.535

Gnomad ASJ exome AF: 0.379

Gnomad EAS exome AF: 0.567

Gnomad FIN exome AF: 0.437

Gnomad NFE exome AF: 0.409

Gnomad OTH exome AF: 0.463

GnomAD4 exome AF: 0.421 AC: 580500 AN: 1380188 Hom.: 123907 Cov.: 31 AF XY: 0.421 AC XY: 287352 AN XY: 682112

African (AFR) AF: 0.467 AC: 14765 AN: 31624

American (AMR) AF: 0.534 AC: 19517 AN: 36524

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 9672 AN: 25094

East Asian (EAS) AF: 0.578 AC: 20817 AN: 36006

South Asian (SAS) AF: 0.470 AC: 37358 AN: 79444

European-Finnish (FIN) AF: 0.426 AC: 14701 AN: 34514

Middle Eastern (MID) AF: 0.490 AC: 2597 AN: 5304

European-Non Finnish (NFE) AF: 0.406 AC: 436307 AN: 1074006

Other (OTH) AF: 0.429 AC: 24766 AN: 57672

GnomAD4 genome AF: 0.436 AC: 66247 AN: 151814 Hom.: 14519 Cov.: 32 AF XY: 0.441 AC XY: 32749 AN XY: 74180

African (AFR) AF: 0.457 AC: 18935 AN: 41398

American (AMR) AF: 0.484 AC: 7391 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 1333 AN: 3470

East Asian (EAS) AF: 0.559 AC: 2862 AN: 5118

South Asian (SAS) AF: 0.478 AC: 2306 AN: 4822

European-Finnish (FIN) AF: 0.432 AC: 4555 AN: 10544

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.404 AC: 27436 AN: 67874

Other (OTH) AF: 0.446 AC: 942 AN: 2112

Alfa AF: 0.416 Hom.: 4315

Bravo AF: 0.442

Asia WGS AF: 0.509 AC: 1770 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Knobloch syndrome (4)
-	-	3	not provided (3)
-	-	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	-0.84
CADD	Benign	0.38
DANN	Benign	0.63
PhyloP100		-6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
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: rs1050351; hg19: chr21-46929467; COSMIC: COSV60586914; COSMIC: COSV60586914;