dbSNP rs104886111: COL4A5:p.Gly426Arg (chrX-108591168-G-A) – ACMG Classification: Pathogenic (17 pts)

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_033380.3(COL4A5):c.1276G>A(p.Gly426Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000331 in 1,208,783 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G426G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000027 ( 0 hom. 1 hem. )

Consequence

COL4A5
NM_033380.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 9.42

Publications

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

COL4A5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_033380.3

PM2

Very rare variant in population databases, with high coverage;

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, 0.993

PP5

Variant X-108591168-G-A is Pathogenic according to our data. Variant chrX-108591168-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 24393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033380.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	NM_033380.3	MANE Select	c.1276G>A	p.Gly426Arg	missense	Exon 20 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.1276G>A	p.Gly426Arg	missense	Exon 20 of 51	NP_000486.1	P29400-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL4A5	ENST00000328300.11	TSL:1 MANE Select	c.1276G>A	p.Gly426Arg	missense	Exon 20 of 53	ENSP00000331902.7	P29400-2
COL4A5	ENST00000483338.1	TSL:1	c.100G>A	p.Gly34Arg	missense	Exon 4 of 20	ENSP00000495685.1	Q49AM6
COL4A5	ENST00000949143.1		c.1276G>A	p.Gly426Arg	missense	Exon 20 of 51	ENSP00000619202.1

Frequencies

GnomAD3 genomes

AF:

0.00000889

AC:

AN:

112532

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000322

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1096251

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362499

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26346

American (AMR)

AF:

0.00

AC:

AN:

35195

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19375

East Asian (EAS)

AF:

0.00

AC:

AN:

30198

South Asian (SAS)

AF:

0.00

AC:

AN:

54066

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3006

European-Non Finnish (NFE)

AF:

0.00000356

AC:

AN:

841578

Other (OTH)

AF:

0.00

AC:

AN:

45961

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.300

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:

0.00000889

AC:

AN:

112532

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34710

show subpopulations

African (AFR)

AF:

0.0000322

AC:

AN:

31031

American (AMR)

AF:

0.00

AC:

AN:

10692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2659

East Asian (EAS)

AF:

0.00

AC:

AN:

3562

South Asian (SAS)

AF:

0.00

AC:

AN:

2759

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6161

Middle Eastern (MID)

AF:

0.00

AC:

AN:

233

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53237

Other (OTH)

AF:

0.00

AC:

AN:

1513

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

X-linked Alport syndrome (6)

not provided (4)

COL4A5-related disorder (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.73

BayesDel_noAF

Pathogenic

0.82

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.7

PhyloP100

9.4

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-6.5

REVEL

Pathogenic

1.0

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MutPred

0.98

Gain of solvent accessibility (P = 6e-04)

MVP

1.0

MPC

0.36

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.98

Mutation Taster

=0/100

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over