rs104886192

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM1PP2BP4_StrongBS1_SupportingBS2

The NM_033380.3(COL4A5):c.2692A>G(p.Met898Val) variant causes a missense change. The variant allele was found at a frequency of 0.000221 in 1,203,910 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 85 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. M898I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., 8 hem., cov: 23)

Exomes 𝑓: 0.00022 ( 0 hom. 77 hem. )

Consequence

COL4A5
NM_033380.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1B:7

Conservation

PhyloP100: 5.54

Publications

5 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 -6 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 1 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=0.053881973).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000196 (22/112245) while in subpopulation SAS AF = 0.00147 (4/2714). AF 95% confidence interval is 0.000503. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3 link	c.2692A>G	p.Met898Val	missense_variant	Exon 32 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.2692A>G	p.Met898Val	missense_variant	Exon 32 of 53	1	NM_033380.3	ENSP00000331902.7	P29400-2
COL4A5	ENST00000483338.1 link	c.1516A>G	p.Met506Val	missense_variant	Exon 16 of 20	1		ENSP00000495685.1	Q49AM6
COL4A5	ENST00000361603.7 link	c.2692A>G	p.Met898Val	missense_variant	Exon 32 of 51	2		ENSP00000354505.2	P29400-1

Frequencies

GnomAD3 genomes

AF:

0.000196

AC:

AN:

112245

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00339

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00147

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000150

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000304

AC:

AN:

181177

AF XY:

0.000425

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00324

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000186

Gnomad OTH exome

AF:

0.000225

GnomAD4 exome

AF:

0.000224

AC:

244

AN:

1091665

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

357385

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26311

American (AMR)

AF:

0.00

AC:

AN:

35170

Ashkenazi Jewish (ASJ)

AF:

0.00326

AC:

AN:

19333

East Asian (EAS)

AF:

0.00

AC:

AN:

30151

South Asian (SAS)

AF:

0.000856

AC:

AN:

53724

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40486

Middle Eastern (MID)

AF:

0.000243

AC:

AN:

4119

European-Non Finnish (NFE)

AF:

0.000137

AC:

115

AN:

836514

Other (OTH)

AF:

0.000414

AC:

AN:

45857

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

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000196

AC:

AN:

112245

Hom.:

Cov.:

AF XY:

0.000233

AC XY:

AN XY:

34395

show subpopulations

African (AFR)

AF:

0.0000324

AC:

AN:

30864

American (AMR)

AF:

0.00

AC:

AN:

10587

Ashkenazi Jewish (ASJ)

AF:

0.00339

AC:

AN:

2655

East Asian (EAS)

AF:

0.00

AC:

AN:

3569

South Asian (SAS)

AF:

0.00147

AC:

AN:

2714

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6195

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.000150

AC:

AN:

53231

Other (OTH)

AF:

0.00

AC:

AN:

1503

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.000444

Hom.:

Bravo

AF:

0.000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000297

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

X-linked Alport syndrome

Pathogenic:2Uncertain:1Benign:2

May 01, 2024

Laboratory of Prof. Karen Avraham, Tel Aviv University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Pathogenic by Deafness Variation Database based on PMID:30773290 -

Aug 30, 2021

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 15, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 11, 2020

Medical Genetics, University of Parma

Significance:Pathogenic

Review Status:flagged submission

Collection Method:clinical testing

- -

not provided

Benign:3

Oct 21, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30773290, 11223851, 25525159, 20378821) -

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COL4A5: BS2 -

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant Alport syndrome

Pathogenic:1

Feb 14, 2019

Yale Center for Mendelian Genomics, Yale University

Significance:Pathogenic

Review Status:flagged submission

Collection Method:literature only

- -

not specified

Benign:1

Aug 01, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: COL4A5 c.2692A>G (p.Met898Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 1203910 control chromosomes, including 85 hemizygotes (gnomAD v4.1.0). c.2692A>G has been reported in the literature in individuals with clinical features of Alport syndrome (e.g., Barker_2001, Connaughton_2019, Uliana_2021), however these report(s) do not provide unequivocal conclusions about association of the variant with Alport Syndrome 1, X-Linked Recessive. Co-occurrences with other pathogenic variant(s) have been reported (INF2 c.353T>A, p.Ile118Asn), providing supporting evidence for a benign role (Connaughton_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11223851, 30773290, 33369211). ClinVar contains an entry for this variant (Variation ID: 24554). Based on the evidence outlined above, the variant was classified as likely benign. -

COL4A5-related disorder

Benign:1

Jun 15, 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

0.093

BayesDel_addAF

Benign

-0.046

BayesDel_noAF

Uncertain

0.080

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.49

.;T;T

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.70

T;T;T

M_CAP

Benign

0.034

MetaRNN

Benign

0.054

T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

0.45

N;N;.

PhyloP100

5.5

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.6

N;N;.

REVEL

Uncertain

0.47

Sift

Benign

0.21

T;T;.

Sift4G

Benign

0.60

T;T;.

Polyphen

0.0050, 0.0030

.;B;B

Vest4

0.17

MVP

0.99

MPC

0.30

ClinPred

0.051

GERP RS

4.5

Varity_R

0.26

gMVP

0.86

Mutation Taster

=62/38

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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