Variant chr3-99794974-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020351.4(COL8A1):c.1073C>T(p.Pro358Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000482 in 1,452,178 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: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

COL8A1
NM_020351.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.25

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18960997).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL8A1	NM_020351.4 link	c.1073C>T	p.Pro358Leu	missense_variant	4/4	ENST00000652472.1	NP_065084.2	P27658
COL8A1	NM_001850.5 link	c.1073C>T	p.Pro358Leu	missense_variant	5/5		NP_001841.2	P27658

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL8A1	ENST00000652472.1 link	c.1073C>T	p.Pro358Leu	missense_variant	4/4		NM_020351.4	ENSP00000498483.1	P27658
COL8A1	ENST00000261037.7 link	c.1073C>T	p.Pro358Leu	missense_variant	5/5	1		ENSP00000261037.3	P27658
COL8A1	ENST00000273342.8 link	c.1073C>T	p.Pro358Leu	missense_variant	4/4	2		ENSP00000273342.3	P27658

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000207

AC:

AN:

241988

Hom.:

AF XY:

0.0000305

AC XY:

AN XY:

131016

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000602

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:

0.0000273

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000482

AC:

AN:

1452178

Hom.:

Cov.:

AF XY:

0.00000693

AC XY:

AN XY:

721822

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000461

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000451

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000113

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

Aug 13, 2021

The c.1073C>T (p.P358L) 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 1073, causing the proline (P) at amino acid position 358 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

0.074

BayesDel_addAF

Benign

-0.041

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Benign

0.64

DEOGEN2

Benign

0.29

T;T

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.83

.;T

M_CAP

Benign

0.058

MetaRNN

Benign

0.19

T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

0.71

N;N

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.27

Sift

Benign

0.46

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.015

B;B

Vest4

0.21

MutPred

0.42

Loss of methylation at K359 (P = 0.0651);Loss of methylation at K359 (P = 0.0651);

MVP

0.88

MPC

0.23

ClinPred

0.12

GERP RS

5.0

Varity_R

0.063

gMVP

0.87

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