rs104886164

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2

The NM_033380.3(COL4A5):c.2215C>G(p.Pro739Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000942 in 1,184,160 control chromosomes in the GnomAD database, including 20 homozygotes. There are 341 hemizygotes in GnomAD. In-silico tool predicts a benign 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. P739H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00060 ( 1 hom., 20 hem., cov: 22)

Exomes 𝑓: 0.00098 ( 19 hom. 321 hem. )

Consequence

COL4A5
NM_033380.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 1.09

Publications

18 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 -10 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain 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=0.020849556).

BP6

Variant X-108603032-C-G is Benign according to our data. Variant chrX-108603032-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 587102.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000605 (67/110815) while in subpopulation EAS AF = 0.0174 (61/3505). AF 95% confidence interval is 0.0139. There are 1 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 20 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3 link	c.2215C>G	p.Pro739Ala	missense_variant	Exon 28 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.2215C>G	p.Pro739Ala	missense_variant	Exon 28 of 53	1	NM_033380.3	ENSP00000331902.7	P29400-2
COL4A5	ENST00000483338.1 link	c.1039C>G	p.Pro347Ala	missense_variant	Exon 12 of 20	1		ENSP00000495685.1	Q49AM6
COL4A5	ENST00000361603.7 link	c.2215C>G	p.Pro739Ala	missense_variant	Exon 28 of 51	2		ENSP00000354505.2	P29400-1

Frequencies

GnomAD3 genomes

AF:

0.000605

AC:

AN:

110770

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000192

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0173

Gnomad SAS

AF:

0.000769

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00134

GnomAD2 exomes

AF:

0.00116

AC:

175

AN:

151506

AF XY:

0.000907

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0134

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000761

GnomAD4 exome

AF:

0.000976

AC:

1048

AN:

1073345

Hom.:

Cov.:

AF XY:

0.000930

AC XY:

321

AN XY:

345329

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25970

American (AMR)

AF:

0.00

AC:

AN:

33751

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18943

East Asian (EAS)

AF:

0.0333

AC:

989

AN:

29658

South Asian (SAS)

AF:

0.000425

AC:

AN:

51740

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39344

Middle Eastern (MID)

AF:

0.000515

AC:

AN:

3880

European-Non Finnish (NFE)

AF:

0.00000970

AC:

AN:

824989

Other (OTH)

AF:

0.000599

AC:

AN:

45070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

115

154

192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000605

AC:

AN:

110815

Hom.:

Cov.:

AF XY:

0.000605

AC XY:

AN XY:

33045

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30541

American (AMR)

AF:

0.000192

AC:

AN:

10424

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.0174

AC:

AN:

3505

South Asian (SAS)

AF:

0.000771

AC:

AN:

2593

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5807

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52892

Other (OTH)

AF:

0.00132

AC:

AN:

1512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.000347

Hom.:

Bravo

AF:

0.000578

ExAC

AF:

0.00111

AC:

132

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

X-linked Alport syndrome

Uncertain:1Benign:2

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Jun 28, 2018

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

COL4A5-related disorder

Benign:1

Aug 09, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.91

.;D;D

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.84

T;T;T

MetaRNN

Benign

0.021

T;T;T

MetaSVM

Uncertain

0.17

MutationAssessor

Benign

1.9

M;M;.

PhyloP100

1.1

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-4.2

D;D;.

REVEL

Uncertain

0.36

Sift

Benign

0.049

D;T;.

Sift4G

Benign

0.082

T;T;.

Polyphen

0.34, 0.20

.;B;B

Vest4

0.17

MVP

0.86

MPC

0.29

ClinPred

0.066

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.14

Mutation Taster

=51/49

polymorphism (auto)

(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