3-99795531-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.1630C>G(p.Pro544Ala) 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. 13/21 in silico tools predict 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: 1.47

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=0.26830864).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL8A1	NM_020351.4	c.1630C>G	p.Pro544Ala	missense_variant	4/4	ENST00000652472.1
COL8A1	NM_001850.5	c.1630C>G	p.Pro544Ala	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL8A1	ENST00000652472.1	c.1630C>G	p.Pro544Ala	missense_variant	4/4		NM_020351.4	P1
COL8A1	ENST00000261037.7	c.1630C>G	p.Pro544Ala	missense_variant	5/5	1		P1
COL8A1	ENST00000273342.8	c.1630C>G	p.Pro544Ala	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 specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 2024

The c.1630C>G (p.P544A) alteration is located in exon 5 (coding exon 2) of the COL8A1 gene. This alteration results from a C to G substitution at nucleotide position 1630, causing the proline (P) at amino acid position 544 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	20
Dann	Benign	0.94
DEOGEN2	Benign	0.32	T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.046
FATHMM_MKL	Benign	0.47	N
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	0.91	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.29
Sift	Benign	0.22	T;T
Sift4G	Benign	0.086	T;T
Polyphen		0.011	B;B
Vest4		0.23
MutPred		0.31		Loss of catalytic residue at P543 (P = 0.0131);Loss of catalytic residue at P543 (P = 0.0131);
MVP		0.89
MPC		0.22
ClinPred		0.15	T
GERP RS		5.8
Varity_R		0.032
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-99514375;