3-99790803-C-T

Variant summary

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

The NM_020351.4(COL8A1):c.121C>T(p.Pro41Ser) variant causes a missense change. 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: 33)
• Consequence: COL8A1 NM_020351.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.17

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=0.3874846).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL8A1	NM_020351.4	c.121C>T	p.Pro41Ser	missense_variant	3/4	ENST00000652472.1
COL8A1	NM_001850.5	c.121C>T	p.Pro41Ser	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL8A1	ENST00000652472.1	c.121C>T	p.Pro41Ser	missense_variant	3/4		NM_020351.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Jan 27, 2022

The c.121C>T (p.P41S) alteration is located in exon 4 (coding exon 1) of the COL8A1 gene. This alteration results from a C to T substitution at nucleotide position 121, causing the proline (P) at amino acid position 41 to be replaced by a serine (S). 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	0.076
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.066	T;T;T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T;.;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Uncertain	0.52	D
MutationTaster	Benign	0.94	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.6	D;N;N;.
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0	D;T;T;T
Polyphen		0.99	.;D;D;.
Vest4		0.46, 0.47
MutPred		0.27		Loss of catalytic residue at P41 (P = 3e-04);Loss of catalytic residue at P41 (P = 3e-04);Loss of catalytic residue at P41 (P = 3e-04);Loss of catalytic residue at P41 (P = 3e-04);
MVP		0.96
MPC		0.23
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.16
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs1559637200; hg19: chr3-99509647;