Variant 3-99794802-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020351.4(COL8A1):c.901A>G(p.Ile301Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000354 in 1,610,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

COL8A1
NM_020351.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.683

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.047768414).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL8A1	NM_020351.4 linkuse as main transcript	c.901A>G	p.Ile301Val	missense_variant	4/4	ENST00000652472.1
COL8A1	NM_001850.5 linkuse as main transcript	c.901A>G	p.Ile301Val	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
COL8A1	ENST00000652472.1 linkuse as main transcript	c.901A>G	p.Ile301Val	missense_variant	4/4		NM_020351.4	P1
COL8A1	ENST00000261037.7 linkuse as main transcript	c.901A>G	p.Ile301Val	missense_variant	5/5	1		P1
COL8A1	ENST00000273342.8 linkuse as main transcript	c.901A>G	p.Ile301Val	missense_variant	4/4	2		P1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

151794

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD3 exomes

AF:

0.0000406

AC:

AN:

246168

Hom.:

AF XY:

0.0000224

AC XY:

AN XY:

133954

show subpopulations

Gnomad AFR exome

AF:

0.000662

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000247

AC:

AN:

1459116

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

725790

show subpopulations

Gnomad4 AFR exome

AF:

0.000839

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000465

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000138

AC:

AN:

151794

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74124

show subpopulations

Gnomad4 AFR

AF:

0.000484

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000967

Hom.:

Bravo

AF:

0.000200

ESP6500AA

AF:

0.000230

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

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

Oct 02, 2023

The c.901A>G (p.I301V) alteration is located in exon 5 (coding exon 2) of the COL8A1 gene. This alteration results from a A to G substitution at nucleotide position 901, causing the isoleucine (I) at amino acid position 301 to be replaced by a valine (V). 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

0.058

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.35

CADD

Benign

8.3

DANN

Benign

0.94

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.18

M_CAP

Benign

0.019

MetaRNN

Benign

0.048

T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.16

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

0.46

N;N

REVEL

Benign

0.14

Sift

Benign

0.65

T;T

Sift4G

Benign

0.44

T;T

Polyphen

0.0

B;B

Vest4

0.060

MVP

0.77

MPC

0.19

ClinPred

0.011

GERP RS

0.54

Varity_R

0.013

gMVP

0.31

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