X-108563912-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 3P and 11B. PM1PP2BP4BP6_ModerateBS1BS2

The NM_033380.3(COL4A5):c.262C>T(p.Pro88Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00002 in 1,201,437 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000017 ( 0 hom. 7 hem. )

Consequence

COL4A5
NM_033380.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 3.86

Publications

3 publications found

Variant links:

Genes affected

COL4A5 (HGNC:2207): (collagen type IV alpha 5 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. Mutations in this gene are associated with X-linked Alport syndrome, also known as hereditary nephritis. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Aug 2010]

COL4A5 Gene-Disease associations (from GenCC):

Alport syndrome
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen, G2P
X-linked Alport syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)

COL4A5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PM1

In a compositionally_biased_region Pro residues (size 18) in uniprot entity CO4A5_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_033380.3

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 538 curated pathogenic missense variants (we use a threshold of 10). The gene has 138 curated benign missense variants. Gene score misZ: 2.4995 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked Alport syndrome, Alport syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.36452103).

BP6

Variant X-108563912-C-T is Benign according to our data. Variant chrX-108563912-C-T is described in ClinVar as [Benign]. Clinvar id is 587092.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000454 (5/110101) while in subpopulation EAS AF = 0.00143 (5/3495). AF 95% confidence interval is 0.000563. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3 link	c.262C>T	p.Pro88Ser	missense_variant	Exon 4 of 53	ENST00000328300.11	NP_203699.1	P29400-2Q49AM6A7MBN3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL4A5	ENST00000328300.11 link	c.262C>T	p.Pro88Ser	missense_variant	Exon 4 of 53	1	NM_033380.3	ENSP00000331902.7	P29400-2
COL4A5	ENST00000361603.7 link	c.262C>T	p.Pro88Ser	missense_variant	Exon 4 of 51	2		ENSP00000354505.2	P29400-1
COL4A5	ENST00000470339.1 link	n.446C>T		non_coding_transcript_exon_variant	Exon 4 of 6	3

Frequencies

GnomAD3 genomes

AF:

0.0000454

AC:

AN:

110101

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00143

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000768

AC:

AN:

182325

AF XY:

0.0000598

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000944

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.0000174

AC:

AN:

1091336

Hom.:

Cov.:

AF XY:

0.0000196

AC XY:

AN XY:

357300

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26273

American (AMR)

AF:

0.00

AC:

AN:

35135

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19284

East Asian (EAS)

AF:

0.000599

AC:

AN:

30051

South Asian (SAS)

AF:

0.00

AC:

AN:

53421

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40453

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4111

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

836791

Other (OTH)

AF:

0.0000218

AC:

AN:

45817

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000454

AC:

AN:

110101

Hom.:

Cov.:

AF XY:

0.0000307

AC XY:

AN XY:

32539

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30299

American (AMR)

AF:

0.00

AC:

AN:

10274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2620

East Asian (EAS)

AF:

0.00143

AC:

AN:

3495

South Asian (SAS)

AF:

0.00

AC:

AN:

2590

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5774

Middle Eastern (MID)

AF:

0.00

AC:

AN:

232

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52666

Other (OTH)

AF:

0.00

AC:

AN:

1466

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

COL4A5-related disorder

Benign:1

Dec 23, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

0.0017

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.55

.;D

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

D;D

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.36

T;T

MetaSVM

Uncertain

0.42

MutationAssessor

Benign

1.7

L;L

PhyloP100

3.9

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.7

D;N

REVEL

Pathogenic

0.65

Sift

Benign

0.79

T;T

Sift4G

Benign

0.41

T;T

Polyphen

0.83

.;P

Vest4

0.81

MutPred

0.28

Gain of phosphorylation at P88 (P = 0.0124);Gain of phosphorylation at P88 (P = 0.0124);

MVP

0.92

MPC

0.30

ClinPred

0.14

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.28

gMVP

0.50

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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X-108563912-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over