chrX-108440099-T-TGAAGGAGCTGCGGGAGCC

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_033380.3(COL4A5):c.-25_-8dupAAGGAGCTGCGGGAGCCG variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.000124 in 1,171,627 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 30 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00078 ( 0 hom., 13 hem., cov: 21)

Exomes 𝑓: 0.000056 ( 0 hom. 17 hem. )

Consequence

COL4A5
NM_033380.3 5_prime_UTR

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 4.04

Publications

0 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 -9 ACMG points.

BP6

Variant X-108440099-T-TGAAGGAGCTGCGGGAGCC is Benign according to our data. Variant chrX-108440099-T-TGAAGGAGCTGCGGGAGCC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 451163.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000776 (85/109520) while in subpopulation AFR AF = 0.00262 (79/30101). AF 95% confidence interval is 0.00216. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3 link	c.-25_-8dupAAGGAGCTGCGGGAGCCG	5_prime_UTR_variant	Exon 1 of 53	ENST00000328300.11	NP_203699.1	P29400-2Q49AM6A7MBN3
COL4A5	NM_000495.5 link	c.-25_-8dupAAGGAGCTGCGGGAGCCG	5_prime_UTR_variant	Exon 1 of 51		NP_000486.1	P29400-1Q49AM6A7MBN3
COL4A5	XM_047441810.1 link	c.-401_-384dupAAGGAGCTGCGGGAGCCG	5_prime_UTR_variant	Exon 1 of 54		XP_047297766.1
COL4A5	XM_047441811.1 link	c.-25_-8dupAAGGAGCTGCGGGAGCCG	5_prime_UTR_variant	Exon 1 of 42		XP_047297767.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11 link	c.-25_-8dupAAGGAGCTGCGGGAGCCG		5_prime_UTR_variant	Exon 1 of 53	1	NM_033380.3	ENSP00000331902.7		P29400-2

Frequencies

GnomAD3 genomes

AF:

0.000777

AC:

AN:

109462

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000294

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:

0.0000190

Gnomad OTH

AF:

0.00137

GnomAD2 exomes

AF:

0.000184

AC:

AN:

173882

AF XY:

0.0000338

show subpopulations

Gnomad AFR exome

AF:

0.00239

Gnomad AMR exome

AF:

0.0000373

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000130

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000565

AC:

AN:

1062107

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

333883

show subpopulations

African (AFR)

AF:

0.00218

AC:

AN:

25724

American (AMR)

AF:

0.0000573

AC:

AN:

34926

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19119

East Asian (EAS)

AF:

0.00

AC:

AN:

30027

South Asian (SAS)

AF:

0.00

AC:

AN:

52664

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40150

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4021

European-Non Finnish (NFE)

AF:

0.00000123

AC:

AN:

810527

Other (OTH)

AF:

0.0000222

AC:

AN:

44949

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000776

AC:

AN:

109520

Hom.:

Cov.:

AF XY:

0.000409

AC XY:

AN XY:

31800

show subpopulations

African (AFR)

AF:

0.00262

AC:

AN:

30101

American (AMR)

AF:

0.000293

AC:

AN:

10226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2618

East Asian (EAS)

AF:

0.00

AC:

AN:

3445

South Asian (SAS)

AF:

0.00

AC:

AN:

2446

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5676

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0000190

AC:

AN:

52634

Other (OTH)

AF:

0.00135

AC:

AN:

1478

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000288

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COL4A5: BS2 -

Aug 01, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This individual is also heterozygous for the c.-25_-8dup18 variant. It has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This regulatory duplication affects both nonconserved nucleotides and nucleotides conserved through mammals. No regulatory variants have been reported in the Human Gene Mutation Database or observed at GeneDx (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

not specified

Uncertain:1

Dec 08, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: COL4A5 c.-25_-8dup18 is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.00018 in 173882 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COL4A5 causing Alport Syndrome 1, X-Linked Recessive (0.00018 vs 0.0046), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.-25_-8dup18 in individuals affected with Alport Syndrome 1, X-Linked Recessive and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Two submitters classified the variant as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

X-linked Alport syndrome

Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

COL4A5-related disorder

Benign:1

Jul 03, 2020

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

PhyloP100

4.0

Mutation Taster

=300/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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chrX-108440099-T-TGAAGGAGCTGCGGGAGCC

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