rs8199

Variant names:

• chr21-45512469-G-A
• rs8199
• NM_001379500.1:c.*71G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-45512469-G-A
• chr21-45512469-G-T

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.*71G>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 0.442 in 1,481,350 control chromosomes in the GnomAD database, including 145,859 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16035 hom., cov: 34)
  • Exomes 𝑓: 0.44 (129824 hom.)
• Consequence: COL18A1 NM_001379500.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.622

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 21-45512469-G-A is Benign according to our data. Variant chr21-45512469-G-A is described in ClinVar as [Benign]. Clinvar id is 340276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.*71G>A		3_prime_UTR_variant	Exon 42 of 42	ENST00000651438.1	NP_001366429.1
SLC19A1	NM_194255.4	c.*3189C>T		downstream_gene_variant		ENST00000311124.9	NP_919231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.*71G>A		3_prime_UTR_variant	Exon 42 of 42		NM_001379500.1	ENSP00000498485.1
SLC19A1	ENST00000311124.9	c.*3189C>T		downstream_gene_variant		1	NM_194255.4	ENSP00000308895.4

Frequencies

GnomAD3 genomes AF: 0.457 AC: 69468 AN: 152048 Hom.: 16028 Cov.: 34

Gnomad AFR AF: 0.508

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.434

Gnomad ASJ AF: 0.398

Gnomad EAS AF: 0.548

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.442

Gnomad MID AF: 0.490

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.475

GnomAD4 exome AF: 0.440 AC: 585244 AN: 1329184 Hom.: 129824 Cov.: 22 AF XY: 0.440 AC XY: 291071 AN XY: 660796

Gnomad4 AFR exome AF: 0.515

Gnomad4 AMR exome AF: 0.433

Gnomad4 ASJ exome AF: 0.401

Gnomad4 EAS exome AF: 0.572

Gnomad4 SAS exome AF: 0.474

Gnomad4 FIN exome AF: 0.437

Gnomad4 NFE exome AF: 0.431

Gnomad4 OTH exome AF: 0.450

GnomAD4 genome AF: 0.457 AC: 69500 AN: 152166 Hom.: 16035 Cov.: 34 AF XY: 0.459 AC XY: 34142 AN XY: 74370

Gnomad4 AFR AF: 0.508

Gnomad4 AMR AF: 0.433

Gnomad4 ASJ AF: 0.398

Gnomad4 EAS AF: 0.549

Gnomad4 SAS AF: 0.489

Gnomad4 FIN AF: 0.442

Gnomad4 NFE AF: 0.427

Gnomad4 OTH AF: 0.473

Alfa AF: 0.307 Hom.: 782

Bravo AF: 0.459

Asia WGS AF: 0.508 AC: 1767 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Knobloch syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.83
CADD	Benign	0.035
DANN	Benign	0.86
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.3

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: rs8199; hg19: chr21-46932383;