ENST00000355480.10:c.120T>C

Variant names:

• chr21-45455650-T-C
• rs914230
• ENST00000355480.10:c.120T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000355480.10(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 ENST00000355480.10 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0690
• Publications: 19 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]

COL18A1 Gene-Disease associations (from GenCC):

• Knobloch syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Knobloch syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet
• hereditary glaucoma, primary closed-angle

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 518320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000355480.10. 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.107-12592T>C		intron	N/A	NP_001366429.1
	COL18A1	NM_130444.3		c.120T>C	p.His40His	synonymous	Exon 1 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.120T>C	p.His40His	synonymous	Exon 1 of 41	NP_085059.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000355480.10	TSL:1	c.120T>C	p.His40His	synonymous	Exon 1 of 41	ENSP00000347665.5
	COL18A1	ENST00000651438.1	MANE Select	c.107-12592T>C		intron	N/A	ENSP00000498485.1
	COL18A1	ENST00000359759.8	TSL:5	c.120T>C	p.His40His	synonymous	Exon 1 of 41	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

GnomAD2 exomes AF: 0.970 AC: 242021 AN: 249428 AF XY: 0.970

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 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

African (AFR) AF: 0.994 AC: 33267 AN: 33480

American (AMR) AF: 0.983 AC: 43972 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.963 AC: 25178 AN: 26134

East Asian (EAS) AF: 1.00 AC: 39697 AN: 39700

South Asian (SAS) AF: 0.990 AC: 85369 AN: 86258

European-Finnish (FIN) AF: 0.956 AC: 50802 AN: 53150

Middle Eastern (MID) AF: 0.982 AC: 5666 AN: 5768

European-Non Finnish (NFE) AF: 0.955 AC: 1062435 AN: 1111996

Other (OTH) AF: 0.964 AC: 58221 AN: 60394

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

African (AFR) AF: 0.992 AC: 41238 AN: 41574

American (AMR) AF: 0.978 AC: 14977 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.967 AC: 3356 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5170 AN: 5170

South Asian (SAS) AF: 0.990 AC: 4782 AN: 4828

European-Finnish (FIN) AF: 0.952 AC: 10115 AN: 10624

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 0.955 AC: 64925 AN: 68014

Other (OTH) AF: 0.976 AC: 2065 AN: 2116

Alfa AF: 0.964 Hom.: 223080

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

May 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 03, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Knobloch syndrome Benign:3

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 23, 2017

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hereditary glaucoma, primary closed-angle Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	6.3
DANN	Benign	0.41
PhyloP100		-0.069
PromoterAI		0.049	Neutral
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: rs914230; hg19: chr21-46875564; COSMIC: COSV108173684;