rs56335679

Variant names:

• chr21-45511078-A-C
• rs56335679
• NM_001379500.1:c.3694-33A>C

Your query was ambiguous. Multiple possible variants found:

• chr21-45511078-A-C
• chr21-45511078-A-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.3694-33A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (12714 hom., cov: 17)
  • Exomes 𝑓: 0.42 (75627 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.82
• 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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 21-45511078-A-C is Benign according to our data. Variant chr21-45511078-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.3694-33A>C		intron_variant	Intron 40 of 41	ENST00000651438.1	NP_001366429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.3694-33A>C		intron_variant	Intron 40 of 41		NM_001379500.1	ENSP00000498485.1

Frequencies

GnomAD3 genomes AF: 0.478 AC: 56155 AN: 117524 Hom.: 12711 Cov.: 17

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.420

Gnomad EAS AF: 0.594

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.508

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.496

GnomAD2 exomes AF: 0.452 AC: 64732 AN: 143278 AF XY: 0.453

Gnomad AFR exome AF: 0.509

Gnomad AMR exome AF: 0.441

Gnomad ASJ exome AF: 0.395

Gnomad EAS exome AF: 0.571

Gnomad FIN exome AF: 0.442

Gnomad NFE exome AF: 0.421

Gnomad OTH exome AF: 0.465

GnomAD4 exome AF: 0.420 AC: 353659 AN: 841384 Hom.: 75627 Cov.: 12 AF XY: 0.425 AC XY: 184547 AN XY: 433862

African (AFR) AF: 0.443 AC: 8982 AN: 20294

American (AMR) AF: 0.439 AC: 14794 AN: 33690

Ashkenazi Jewish (ASJ) AF: 0.427 AC: 8534 AN: 19978

East Asian (EAS) AF: 0.628 AC: 18763 AN: 29890

South Asian (SAS) AF: 0.477 AC: 32672 AN: 68426

European-Finnish (FIN) AF: 0.482 AC: 19681 AN: 40814

Middle Eastern (MID) AF: 0.503 AC: 2205 AN: 4382

European-Non Finnish (NFE) AF: 0.395 AC: 231209 AN: 586008

Other (OTH) AF: 0.444 AC: 16819 AN: 37902

GnomAD4 genome AF: 0.478 AC: 56163 AN: 117566 Hom.: 12714 Cov.: 17 AF XY: 0.483 AC XY: 26897 AN XY: 55650

African (AFR) AF: 0.525 AC: 14720 AN: 28026

American (AMR) AF: 0.471 AC: 5297 AN: 11246

Ashkenazi Jewish (ASJ) AF: 0.420 AC: 1282 AN: 3056

East Asian (EAS) AF: 0.595 AC: 2293 AN: 3852

South Asian (SAS) AF: 0.535 AC: 1872 AN: 3496

European-Finnish (FIN) AF: 0.500 AC: 3155 AN: 6304

Middle Eastern (MID) AF: 0.512 AC: 124 AN: 242

European-Non Finnish (NFE) AF: 0.446 AC: 26302 AN: 58936

Other (OTH) AF: 0.493 AC: 818 AN: 1660

Alfa AF: 0.424 Hom.: 2244

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely 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

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.14
DANN	Benign	0.13
PhyloP100		-1.8
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: rs56335679; hg19: chr21-46930992; COSMIC: COSV60589788; COSMIC: COSV60589788;