3-99790956-G-A

Position:

• chr3-99790956-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020351.4(COL8A1):​c.274G>A​(p.Glu92Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 4.99

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL8A1	NM_020351.4	c.274G>A	p.Glu92Lys	missense_variant	3/4	ENST00000652472.1	NP_065084.2
COL8A1	NM_001850.5	c.274G>A	p.Glu92Lys	missense_variant	4/5		NP_001841.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL8A1	ENST00000652472.1	c.274G>A	p.Glu92Lys	missense_variant	3/4		NM_020351.4	ENSP00000498483.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

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

Feb 16, 2023

The c.274G>A (p.E92K) alteration is located in exon 4 (coding exon 1) of the COL8A1 gene. This alteration results from a G to A substitution at nucleotide position 274, causing the glutamic acid (E) at amino acid position 92 to be replaced by a lysine (K). 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	0.30
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	T;T;T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.88	D;.;D;D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Uncertain	0.085	D
MutationAssessor	Uncertain	2.2	.;M;M;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.8	D;N;N;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.0080	D;D;D;.
Sift4G	Pathogenic	0.0	D;T;T;T
Polyphen		0.92	.;P;P;.
Vest4		0.44, 0.44
MutPred		0.36		Gain of methylation at E92 (P = 0.0014);Gain of methylation at E92 (P = 0.0014);Gain of methylation at E92 (P = 0.0014);Gain of methylation at E92 (P = 0.0014);
MVP		0.96
MPC		0.25
ClinPred		0.95	D
GERP RS		5.9
Varity_R		0.13
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-99509800; COSMIC: COSV53741739;