chr21-45455650-T-C

Position:

• chr21-45455650-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_130444.3(COL18A1):​c.120T>C​(p.His40His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.962 in 1,613,912 control chromosomes in the GnomAD database, including 746,811 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (71767 hom., cov: 34)
  • Exomes 𝑓: 0.96 (675044 hom.)
• Consequence: COL18A1 NM_130444.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0690

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 21-45455650-T-C is Benign according to our data. Variant chr21-45455650-T-C is described in ClinVar as [Benign]. Clinvar id is 518320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45455650-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.069 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.984 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.107-12592T>C		intron_variant		ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3	c.120T>C	p.His40His	synonymous_variant	1/41		NP_569711.2
COL18A1	NM_030582.4	c.120T>C	p.His40His	synonymous_variant	1/41		NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000355480.10	c.120T>C	p.His40His	synonymous_variant	1/41	1		ENSP00000347665.5
COL18A1	ENST00000651438.1	c.107-12592T>C		intron_variant			NM_001379500.1	ENSP00000498485.1
COL18A1	ENST00000359759.8	c.120T>C	p.His40His	synonymous_variant	1/41	5		ENSP00000352798.4

Frequencies

GnomAD3 genomes AF: 0.970 AC: 147700 AN: 152194 Hom.: 71705 Cov.: 34

Gnomad AFR AF: 0.992

Gnomad AMI AF: 0.992

Gnomad AMR AF: 0.978

Gnomad ASJ AF: 0.967

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.990

Gnomad FIN AF: 0.952

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.955

Gnomad OTH AF: 0.975

GnomAD3 exomes AF: 0.970 AC: 242021 AN: 249428 Hom.: 117452 AF XY: 0.970 AC XY: 131337 AN XY: 135368

Gnomad AFR exome AF: 0.993

Gnomad AMR exome AF: 0.984

Gnomad ASJ exome AF: 0.963

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.991

Gnomad FIN exome AF: 0.956

Gnomad NFE exome AF: 0.956

Gnomad OTH exome AF: 0.965

GnomAD4 exome AF: 0.961 AC: 1404607 AN: 1461600 Hom.: 675044 Cov.: 86 AF XY: 0.962 AC XY: 699397 AN XY: 727120

Gnomad4 AFR exome AF: 0.994

Gnomad4 AMR exome AF: 0.983

Gnomad4 ASJ exome AF: 0.963

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.990

Gnomad4 FIN exome AF: 0.956

Gnomad4 NFE exome AF: 0.955

Gnomad4 OTH exome AF: 0.964

GnomAD4 genome AF: 0.971 AC: 147821 AN: 152312 Hom.: 71767 Cov.: 34 AF XY: 0.971 AC XY: 72321 AN XY: 74466

Gnomad4 AFR AF: 0.992

Gnomad4 AMR AF: 0.978

Gnomad4 ASJ AF: 0.967

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.990

Gnomad4 FIN AF: 0.952

Gnomad4 NFE AF: 0.955

Gnomad4 OTH AF: 0.976

Alfa AF: 0.961 Hom.: 137006

Bravo AF: 0.974

Asia WGS AF: 0.995 AC: 3460 AN: 3478

EpiCase AF: 0.961

EpiControl AF: 0.961

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Knobloch syndrome Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jan 23, 2017	- -

Glaucoma, primary closed-angle Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	6.3
DANN	Benign	0.41

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: rs914230; hg19: chr21-46875564;