21-45512738-G-A

Position:

• chr21-45512738-G-A

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.*340G>A		3_prime_UTR_variant	42/42	ENST00000651438.1	NP_001366429.1
SLC19A1	NM_194255.4	c.*2920C>T		3_prime_UTR_variant	6/6	ENST00000311124.9	NP_919231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.*340G>A		3_prime_UTR_variant	42/42		NM_001379500.1	ENSP00000498485.1
SLC19A1	ENST00000311124.9	c.*2920C>T		3_prime_UTR_variant	6/6	1	NM_194255.4	ENSP00000308895.4

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

Gnomad4 AFR exome AF: 0.530

Gnomad4 AMR exome AF: 0.429

Gnomad4 ASJ exome AF: 0.405

Gnomad4 EAS exome AF: 0.578

Gnomad4 SAS exome AF: 0.475

Gnomad4 FIN exome AF: 0.444

Gnomad4 NFE exome AF: 0.433

Gnomad4 OTH exome AF: 0.452

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

Gnomad4 AFR AF: 0.526

Gnomad4 AMR AF: 0.436

Gnomad4 ASJ AF: 0.399

Gnomad4 EAS AF: 0.553

Gnomad4 SAS AF: 0.494

Gnomad4 FIN AF: 0.442

Gnomad4 NFE AF: 0.428

Gnomad4 OTH AF: 0.482

Alfa AF: 0.434 Hom.: 10257

Bravo AF: 0.466

Asia WGS AF: 0.520 AC: 1806 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Knobloch syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.4
DANN	Benign	0.84
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs7867; hg19: chr21-46932652; COSMIC: COSV60591014; COSMIC: COSV60591014;