3-99794574-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020351.4(COL8A1):c.673C>G(p.Arg225Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL8A1 NM_020351.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.75

Genes affected

COL8A1 (HGNC:2215): (collagen type VIII alpha 1 chain) This gene encodes one of the two alpha chains of type VIII collagen. The gene product is a short chain collagen and a major component of the basement membrane of the corneal endothelium. The type VIII collagen fibril can be either a homo- or a heterotrimer. Alternatively spliced transcript variants encoding the same protein have been observed. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32685745).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL8A1	NM_020351.4	c.673C>G	p.Arg225Gly	missense_variant	4/4	ENST00000652472.1
COL8A1	NM_001850.5	c.673C>G	p.Arg225Gly	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL8A1	ENST00000652472.1	c.673C>G	p.Arg225Gly	missense_variant	4/4		NM_020351.4	P1
COL8A1	ENST00000261037.7	c.673C>G	p.Arg225Gly	missense_variant	5/5	1		P1
COL8A1	ENST00000273342.8	c.673C>G	p.Arg225Gly	missense_variant	4/4	2		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 12, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.60	D;D
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Uncertain	0.099	D
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	0.65	N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.090	T;T
Sift4G	Uncertain	0.028	D;D
Polyphen		0.080	B;B
Vest4		0.20
MutPred		0.47		Gain of relative solvent accessibility (P = 0.0275);Gain of relative solvent accessibility (P = 0.0275);
MVP		0.91
MPC		0.29
ClinPred		0.69	D
GERP RS		1.5
Varity_R		0.20
gMVP		0.75

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: rs980591241; hg19: chr3-99513418;