rs78487064

Variant names:

• chr21-45509639-C-G
• rs78487064
• NM_001379500.1:c.3495+38C>G

Your query was ambiguous. Multiple possible variants found:

• chr21-45509639-C-G
• chr21-45509639-C-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.3495+38C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,093,156 control chromosomes in the GnomAD database, including 11,637 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2286 hom., cov: 34)
  • Exomes 𝑓: 0.14 (9351 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.459
• 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]

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=-0.82).
• BP6: Variant 21-45509639-C-G is Benign according to our data. Variant chr21-45509639-C-G is described in ClinVar as Benign. ClinVar VariationId is 261911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.231 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.3495+38C>G		intron	N/A	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.4740+38C>G		intron	N/A	NP_569711.2
	COL18A1	NM_030582.4		c.4035+38C>G		intron	N/A	NP_085059.2	A0AAG2UXZ5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.3495+38C>G		intron	N/A	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.4035+38C>G		intron	N/A	ENSP00000347665.5	P39060-1
	SLC19A1	ENST00000567670.5	TSL:1	c.1294-11027G>C		intron	N/A	ENSP00000457278.1	H3BTQ3

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25344 AN: 152042 Hom.: 2281 Cov.: 34

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.0600

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.167

GnomAD2 exomes AF: 0.140 AC: 18146 AN: 129336 AF XY: 0.137

Gnomad AFR exome AF: 0.238

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.0560

Gnomad FIN exome AF: 0.143

Gnomad NFE exome AF: 0.136

Gnomad OTH exome AF: 0.146

GnomAD4 exome AF: 0.138 AC: 130087 AN: 940996 Hom.: 9351 Cov.: 13 AF XY: 0.136 AC XY: 65636 AN XY: 481802

African (AFR) AF: 0.237 AC: 5516 AN: 23286

American (AMR) AF: 0.195 AC: 6864 AN: 35166

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 2917 AN: 22352

East Asian (EAS) AF: 0.0622 AC: 2104 AN: 33828

South Asian (SAS) AF: 0.111 AC: 7806 AN: 70580

European-Finnish (FIN) AF: 0.146 AC: 4890 AN: 33568

Middle Eastern (MID) AF: 0.134 AC: 560 AN: 4192

European-Non Finnish (NFE) AF: 0.138 AC: 93215 AN: 674730

Other (OTH) AF: 0.144 AC: 6215 AN: 43294

GnomAD4 genome AF: 0.167 AC: 25381 AN: 152160 Hom.: 2286 Cov.: 34 AF XY: 0.164 AC XY: 12198 AN XY: 74378

African (AFR) AF: 0.235 AC: 9740 AN: 41492

American (AMR) AF: 0.200 AC: 3061 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 457 AN: 3470

East Asian (EAS) AF: 0.0597 AC: 309 AN: 5174

South Asian (SAS) AF: 0.102 AC: 491 AN: 4830

European-Finnish (FIN) AF: 0.143 AC: 1516 AN: 10606

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.137 AC: 9333 AN: 67966

Other (OTH) AF: 0.166 AC: 350 AN: 2112

Alfa AF: 0.151 Hom.: 279

Bravo AF: 0.174

Asia WGS AF: 0.0890 AC: 311 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.8
DANN	Benign	0.57
PhyloP100		-0.46
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: rs78487064; hg19: chr21-46929553;