NM_001379500.1:c.*340G>A

Variant names:

• chr21-45512738-G-A
• rs7867
• NM_001379500.1:c.*340G>A

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.*340G>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 0.455 in 395,724 control chromosomes in the GnomAD database, including 41,587 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16479 hom., cov: 33)
  • Exomes 𝑓: 0.45 (25108 hom.)
• Consequence: COL18A1 NM_001379500.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.473
• Publications: 13 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=-0.85).
• BP6: Variant 21-45512738-G-A is Benign according to our data. Variant chr21-45512738-G-A is described in ClinVar as Benign. ClinVar VariationId is 340283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.536 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.*340G>A		3_prime_UTR	Exon 42 of 42	NP_001366429.1	P39060-2
	SLC19A1	NM_194255.4	MANE Select	c.*2920C>T		3_prime_UTR	Exon 6 of 6	NP_919231.1	P41440-1
	COL18A1	NM_130444.3		c.*340G>A		3_prime_UTR	Exon 41 of 41	NP_569711.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.*340G>A		3_prime_UTR	Exon 42 of 42	ENSP00000498485.1	P39060-2
	SLC19A1	ENST00000311124.9	TSL:1 MANE Select	c.*2920C>T		3_prime_UTR	Exon 6 of 6	ENSP00000308895.4	P41440-1
	COL18A1	ENST00000355480.10	TSL:1	c.*340G>A		3_prime_UTR	Exon 41 of 41	ENSP00000347665.5	P39060-1

Frequencies

GnomAD3 genomes AF: 0.463 AC: 70309 AN: 151838 Hom.: 16467 Cov.: 33

Gnomad AFR AF: 0.526

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.437

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.552

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.442

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.485

GnomAD4 exome AF: 0.450 AC: 109812 AN: 243768 Hom.: 25108 Cov.: 0 AF XY: 0.451 AC XY: 58562 AN XY: 129766

African (AFR) AF: 0.530 AC: 3878 AN: 7320

American (AMR) AF: 0.429 AC: 4331 AN: 10084

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 2777 AN: 6854

East Asian (EAS) AF: 0.578 AC: 6916 AN: 11962

South Asian (SAS) AF: 0.475 AC: 18351 AN: 38668

European-Finnish (FIN) AF: 0.444 AC: 5389 AN: 12124

Middle Eastern (MID) AF: 0.530 AC: 517 AN: 976

European-Non Finnish (NFE) AF: 0.433 AC: 61755 AN: 142718

Other (OTH) AF: 0.452 AC: 5898 AN: 13062

GnomAD4 genome AF: 0.463 AC: 70349 AN: 151956 Hom.: 16479 Cov.: 33 AF XY: 0.465 AC XY: 34514 AN XY: 74252

African (AFR) AF: 0.526 AC: 21790 AN: 41428

American (AMR) AF: 0.436 AC: 6658 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 1384 AN: 3470

East Asian (EAS) AF: 0.553 AC: 2852 AN: 5158

South Asian (SAS) AF: 0.494 AC: 2383 AN: 4820

European-Finnish (FIN) AF: 0.442 AC: 4659 AN: 10548

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.428 AC: 29086 AN: 67930

Other (OTH) AF: 0.482 AC: 1018 AN: 2112

Alfa AF: 0.443 Hom.: 34122

Bravo AF: 0.466

Asia WGS AF: 0.520 AC: 1806 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Knobloch syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.4
DANN	Benign	0.84
PhyloP100		-0.47
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
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: rs7867; hg19: chr21-46932652; COSMIC: COSV60591014; COSMIC: COSV60591014;