X-108686096-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 7P and 9B. PM1PM5PP2PP3_ModerateBP6BS1BS2

The NM_033380.3(COL4A5):c.4282C>T(p.Arg1428Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00085 in 1,208,447 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 340 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1428H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., 11 hem., cov: 23)

Exomes 𝑓: 0.00090 ( 0 hom. 329 hem. )

Consequence

COL4A5
NM_033380.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 1.32

Publications

9 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: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_033380.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-108686097-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1030828.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.902

BP6

Variant X-108686096-C-T is Benign according to our data. Variant chrX-108686096-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 242725.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000351 (39/111138) while in subpopulation NFE AF = 0.000604 (32/52998). AF 95% confidence interval is 0.000439. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3 link	c.4282C>T	p.Arg1428Cys	missense_variant	Exon 48 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11 link	c.4282C>T	p.Arg1428Cys	missense_variant	Exon 48 of 53	1	NM_033380.3	ENSP00000331902.7

Frequencies

GnomAD3 genomes

AF:

0.000351

AC:

AN:

111085

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000131

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000283

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000168

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000604

Gnomad OTH

AF:

0.000670

GnomAD2 exomes

AF:

0.000345

AC:

AN:

182384

AF XY:

0.000388

show subpopulations

Gnomad AFR exome

AF:

0.000153

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000188

Gnomad NFE exome

AF:

0.000701

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.000900

AC:

988

AN:

1097309

Hom.:

Cov.:

AF XY:

0.000907

AC XY:

329

AN XY:

362753

show subpopulations

African (AFR)

AF:

0.000152

AC:

AN:

26373

American (AMR)

AF:

0.0000284

AC:

AN:

35164

Ashkenazi Jewish (ASJ)

AF:

0.000103

AC:

AN:

19373

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30176

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54066

European-Finnish (FIN)

AF:

0.000370

AC:

AN:

40490

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4072

European-Non Finnish (NFE)

AF:

0.00111

AC:

932

AN:

841541

Other (OTH)

AF:

0.000695

AC:

AN:

46054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

103

138

172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000351

AC:

AN:

111138

Hom.:

Cov.:

AF XY:

0.000330

AC XY:

AN XY:

33344

show subpopulations

African (AFR)

AF:

0.000131

AC:

AN:

30570

American (AMR)

AF:

0.00

AC:

AN:

10454

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2634

East Asian (EAS)

AF:

0.000284

AC:

AN:

3516

South Asian (SAS)

AF:

0.00

AC:

AN:

2614

European-Finnish (FIN)

AF:

0.000168

AC:

AN:

5945

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.000604

AC:

AN:

52998

Other (OTH)

AF:

0.000662

AC:

AN:

1511

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000473

Hom.:

Bravo

AF:

0.000431

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000743

AC:

ExAC

AF:

0.000329

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000595

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Jun 08, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 7706490, 9195222) -

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

X-linked Alport syndrome

Benign:3

Jul 22, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 04, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 17, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

COL4A5-related disorder

Uncertain:1

Sep 05, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The COL4A5 c.4264C>T variant is predicted to result in the amino acid substitution p.Arg1422Cys. This variant was reported in two individuals with Alport syndrome along with a second potentially pathogenic variant (Guo. 1995. PubMed ID: 7706490; Table S3, Domingo-Gallego. 2022. PubMed ID: 33532864). This variant is reported in 0.067% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including 28 hemizygous individuals (http://gnomad.broadinstitute.org/variant/X-107929326-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

.;D

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.83

T;T

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Uncertain

0.35

MutationAssessor

Uncertain

2.1

.;M

PhyloP100

1.3

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.8

D;D

REVEL

Uncertain

0.60

Sift

Uncertain

0.015

D;D

Sift4G

Benign

0.065

T;T

Polyphen

0.40

.;B

Vest4

0.91

MVP

0.97

MPC

1.2

ClinPred

0.11

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.37

gMVP

0.53

Mutation Taster

=89/11

polymorphism

(source)

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

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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