dbSNP rs104886192: COL4A5:p.Met898Val (chrX-108621817-A-G) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 3P and 12B. PM1PP2BP4_StrongBS1BS2

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: 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: Benign. The variant received -9 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, 4 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.

BS2

High Hemizygotes in GnomAd4 at 8 XL gene

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.2692A>G	p.Met898Val	missense	Exon 32 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.2692A>G	p.Met898Val	missense	Exon 32 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.2692A>G	p.Met898Val	missense	Exon 32 of 53	ENSP00000331902.7	P29400-2
COL4A5	ENST00000483338.1	TSL:1	c.1516A>G	p.Met506Val	missense	Exon 16 of 20	ENSP00000495685.1	Q49AM6
COL4A5	ENST00000949143.1		c.2692A>G	p.Met898Val	missense	Exon 32 of 51	ENSP00000619202.1

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

X-linked Alport syndrome (5)

not provided (3)

Autosomal dominant Alport syndrome (1)

COL4A5-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

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

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.70

M_CAP

Benign

0.034

MetaRNN

Benign

0.054

MetaSVM

Benign

-0.57

MutationAssessor

Benign

0.45

PhyloP100

5.5

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.47

Sift

Benign

0.21

Sift4G

Benign

0.60

Polyphen

0.0050

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

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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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over