Variant 3-99795463-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_020351.4(COL8A1):c.1562C>T(p.Pro521Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000072 in 1,527,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000058 ( 0 hom. )

Consequence

COL8A1
NM_020351.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.668

Variant links:

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]

COL8A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.3719705).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL8A1	NM_020351.4 linkuse as main transcript	c.1562C>T	p.Pro521Leu	missense_variant	4/4	ENST00000652472.1
COL8A1	NM_001850.5 linkuse as main transcript	c.1562C>T	p.Pro521Leu	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
COL8A1	ENST00000652472.1 linkuse as main transcript	c.1562C>T	p.Pro521Leu	missense_variant	4/4		NM_020351.4	P1
COL8A1	ENST00000261037.7 linkuse as main transcript	c.1562C>T	p.Pro521Leu	missense_variant	5/5	1		P1
COL8A1	ENST00000273342.8 linkuse as main transcript	c.1562C>T	p.Pro521Leu	missense_variant	4/4	2		P1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151810

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000582

AC:

AN:

1375358

Hom.:

Cov.:

AF XY:

0.00000591

AC XY:

AN XY:

676316

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000279

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000468

Gnomad4 OTH exome

AF:

0.0000354

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151810

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74132

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2023

The c.1562C>T (p.P521L) alteration is located in exon 5 (coding exon 2) of the COL8A1 gene. This alteration results from a C to T substitution at nucleotide position 1562, causing the proline (P) at amino acid position 521 to be replaced by a leucine (L). 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

0.075

BayesDel_addAF

Uncertain

0.088

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.60

D;D

Eigen

Benign

-0.072

Eigen_PC

Benign

-0.047

FATHMM_MKL

Benign

0.37

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.37

T;T

MetaSVM

Uncertain

0.74

MutationAssessor

Uncertain

2.1

M;M

MutationTaster

Benign

0.88

D;D

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.6

D;D

REVEL

Uncertain

0.40

Sift

Uncertain

0.014

D;D

Sift4G

Benign

0.072

T;T

Polyphen

0.50

P;P

Vest4

0.27

MutPred

0.38

Loss of relative solvent accessibility (P = 0.0404);Loss of relative solvent accessibility (P = 0.0404);

MVP

0.91

MPC

0.23

ClinPred

0.35

GERP RS

4.9

Varity_R

0.067

gMVP

0.41

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over