21-45512201-G-T

Variant names:

• chr21-45512201-G-T
• rs61736805
• NM_001379500.1:c.3823G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001379500.1(COL18A1):​c.3823G>T​(p.Val1275Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00409 in 1,612,314 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1275M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (32 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (82 hom.)
• Consequence: COL18A1 NM_001379500.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.14
• Publications: 7 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 (MetaRNN=0.011089116).
• BP6: Variant 21-45512201-G-T is Benign according to our data. Variant chr21-45512201-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0126 (1922/152342) while in subpopulation AFR AF = 0.0402 (1672/41576). AF 95% confidence interval is 0.0386. There are 32 homozygotes in GnomAd4. There are 922 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	NM_001379500.1	MANE Select	c.3823G>T	p.Val1275Leu	missense	Exon 42 of 42	NP_001366429.1
	COL18A1	NM_130444.3		c.5068G>T	p.Val1690Leu	missense	Exon 41 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.4363G>T	p.Val1455Leu	missense	Exon 41 of 41	NP_085059.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.3823G>T	p.Val1275Leu	missense	Exon 42 of 42	ENSP00000498485.1
	COL18A1	ENST00000355480.10	TSL:1	c.4363G>T	p.Val1455Leu	missense	Exon 41 of 41	ENSP00000347665.5
	SLC19A1	ENST00000567670.5	TSL:1	c.1294-13589C>A		intron	N/A	ENSP00000457278.1

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1906 AN: 152224 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.0399

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00649 AC: 1574 AN: 242486 AF XY: 0.00669

Gnomad AFR exome AF: 0.0405

Gnomad AMR exome AF: 0.00230

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00696

Gnomad FIN exome AF: 0.000144

Gnomad NFE exome AF: 0.000608

Gnomad OTH exome AF: 0.00372

GnomAD4 exome AF: 0.00320 AC: 4678 AN: 1459972 Hom.: 82 Cov.: 32 AF XY: 0.00362 AC XY: 2628 AN XY: 726296

African (AFR) AF: 0.0459 AC: 1535 AN: 33460

American (AMR) AF: 0.00249 AC: 111 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00260 AC: 103 AN: 39644

South Asian (SAS) AF: 0.0207 AC: 1784 AN: 86100

European-Finnish (FIN) AF: 0.000248 AC: 13 AN: 52374

Middle Eastern (MID) AF: 0.00572 AC: 33 AN: 5766

European-Non Finnish (NFE) AF: 0.000666 AC: 740 AN: 1111598

Other (OTH) AF: 0.00595 AC: 359 AN: 60286

GnomAD4 genome AF: 0.0126 AC: 1922 AN: 152342 Hom.: 32 Cov.: 33 AF XY: 0.0124 AC XY: 922 AN XY: 74504

African (AFR) AF: 0.0402 AC: 1672 AN: 41576

American (AMR) AF: 0.00431 AC: 66 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00540 AC: 28 AN: 5188

South Asian (SAS) AF: 0.0201 AC: 97 AN: 4830

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10632

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 68022

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00596 Hom.: 25

Bravo AF: 0.0140

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0363 AC: 150

ESP6500EA AF: 0.000954 AC: 8

ExAC AF: 0.00748 AC: 902

EpiCase AF: 0.000654

EpiControl AF: 0.000891

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.084
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.18
Sift	Uncertain	0.010	D
Sift4G	Benign	0.23	T
Polyphen		0.037	B
Vest4		0.13
MutPred		0.70		Loss of sheet (P = 0.0817)
MVP		0.43
MPC		0.31
ClinPred		0.016	T
GERP RS		3.2
Varity_R		0.50
gMVP		0.64
Mutation Taster		=87/13	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: rs61736805; hg19: chr21-46932115; COSMIC: COSV99051955; COSMIC: COSV99051955;