rs9980939

Variant names:

• chr21-45510096-A-G
• rs9980939
• NM_001379500.1:c.3528A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001379500.1(COL18A1):​c.3528A>G​(p.Ser1176Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00955 in 1,588,520 control chromosomes in the GnomAD database, including 144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (45 hom., cov: 34)
  • Exomes 𝑓: 0.0087 (99 hom.)
• Consequence: COL18A1 NM_001379500.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -5.80
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.146).
• BP6: Variant 21-45510096-A-G is Benign according to our data. Variant chr21-45510096-A-G is described in ClinVar as Benign. ClinVar VariationId is 261912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.8 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.018 (2742/152236) while in subpopulation AFR AF = 0.0458 (1902/41546). AF 95% confidence interval is 0.0441. There are 45 homozygotes in GnomAd4. There are 1258 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 45 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.3528A>G	p.Ser1176Ser	synonymous_variant	Exon 40 of 42	ENST00000651438.1	NP_001366429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.3528A>G	p.Ser1176Ser	synonymous_variant	Exon 40 of 42		NM_001379500.1	ENSP00000498485.1

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2736 AN: 152118 Hom.: 44 Cov.: 34

Gnomad AFR AF: 0.0458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0157

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.00762

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.00968 AC: 1925 AN: 198864 AF XY: 0.00975

Gnomad AFR exome AF: 0.0483

Gnomad AMR exome AF: 0.00812

Gnomad ASJ exome AF: 0.00287

Gnomad EAS exome AF: 0.000325

Gnomad FIN exome AF: 0.0000649

Gnomad NFE exome AF: 0.00799

Gnomad OTH exome AF: 0.00681

GnomAD4 exome AF: 0.00865 AC: 12428 AN: 1436284 Hom.: 99 Cov.: 32 AF XY: 0.00869 AC XY: 6194 AN XY: 713020

African (AFR) AF: 0.0475 AC: 1562 AN: 32918

American (AMR) AF: 0.00874 AC: 371 AN: 42428

Ashkenazi Jewish (ASJ) AF: 0.00218 AC: 56 AN: 25726

East Asian (EAS) AF: 0.000339 AC: 13 AN: 38292

South Asian (SAS) AF: 0.0151 AC: 1262 AN: 83346

European-Finnish (FIN) AF: 0.000192 AC: 9 AN: 46982

Middle Eastern (MID) AF: 0.0219 AC: 107 AN: 4890

European-Non Finnish (NFE) AF: 0.00767 AC: 8451 AN: 1102322

Other (OTH) AF: 0.0101 AC: 597 AN: 59380

GnomAD4 genome AF: 0.0180 AC: 2742 AN: 152236 Hom.: 45 Cov.: 34 AF XY: 0.0169 AC XY: 1258 AN XY: 74442

African (AFR) AF: 0.0458 AC: 1902 AN: 41546

American (AMR) AF: 0.0123 AC: 188 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5172

South Asian (SAS) AF: 0.0159 AC: 77 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.00761 AC: 517 AN: 67966

Other (OTH) AF: 0.0180 AC: 38 AN: 2116

Alfa AF: 0.0102 Hom.: 2

Bravo AF: 0.0203

Asia WGS AF: 0.00983 AC: 34 AN: 3474

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: 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	-0.91
CADD	Benign	0.042
DANN	Benign	0.31
PhyloP100		-5.8
Mutation Taster		=96/4	polymorphism

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: rs9980939; hg19: chr21-46930010;