rs104886089

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_033380.3(COL4A5):c.1033-15delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00413 in 1,093,951 control chromosomes in the GnomAD database, including 15 homozygotes. There are 1,338 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.0045 ( 4 hom., 129 hem., cov: 21)

Exomes 𝑓: 0.0041 ( 11 hom. 1209 hem. )

Consequence

COL4A5
NM_033380.3 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.409

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 -16 ACMG points.

BP6

Variant X-108586590-AT-A is Benign according to our data. Variant chrX-108586590-AT-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 24358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00446 (474/106363) while in subpopulation NFE AF = 0.00719 (367/51075). AF 95% confidence interval is 0.00658. There are 4 homozygotes in GnomAd4. There are 129 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3 link	c.1033-15delT		intron_variant	Intron 18 of 52	ENST00000328300.11	NP_203699.1	P29400-2Q49AM6A7MBN3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL4A5	ENST00000328300.11 link	c.1033-24delT	intron_variant	Intron 18 of 52	1	NM_033380.3	ENSP00000331902.7	P29400-2
COL4A5	ENST00000483338.1 link	c.-144-24delT	intron_variant	Intron 2 of 19	1		ENSP00000495685.1	Q49AM6
COL4A5	ENST00000361603.7 link	c.1033-24delT	intron_variant	Intron 18 of 50	2		ENSP00000354505.2	P29400-1

Frequencies

GnomAD3 genomes

AF:

0.00446

AC:

474

AN:

106330

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00670

Gnomad EAS

AF:

0.000291

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00694

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00718

Gnomad OTH

AF:

0.00140

GnomAD2 exomes

AF:

0.00681

AC:

911

AN:

133794

AF XY:

0.00698

show subpopulations

Gnomad AFR exome

AF:

0.00206

Gnomad AMR exome

AF:

0.00291

Gnomad ASJ exome

AF:

0.00487

Gnomad EAS exome

AF:

0.00117

Gnomad FIN exome

AF:

0.0132

Gnomad NFE exome

AF:

0.00854

Gnomad OTH exome

AF:

0.0130

GnomAD4 exome

AF:

0.00410

AC:

4046

AN:

987588

Hom.:

Cov.:

AF XY:

0.00383

AC XY:

1209

AN XY:

315924

show subpopulations

African (AFR)

AF:

0.00119

AC:

AN:

23479

American (AMR)

AF:

0.00228

AC:

AN:

32059

Ashkenazi Jewish (ASJ)

AF:

0.00323

AC:

AN:

17340

East Asian (EAS)

AF:

0.000328

AC:

AN:

27444

South Asian (SAS)

AF:

0.00351

AC:

169

AN:

48211

European-Finnish (FIN)

AF:

0.0113

AC:

427

AN:

37696

Middle Eastern (MID)

AF:

0.000806

AC:

AN:

3722

European-Non Finnish (NFE)

AF:

0.00411

AC:

3109

AN:

756324

Other (OTH)

AF:

0.00416

AC:

172

AN:

41313

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

130

259

389

518

648

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

252

336

420

<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:

0.00446

AC:

474

AN:

106363

Hom.:

Cov.:

AF XY:

0.00428

AC XY:

129

AN XY:

30135

show subpopulations

African (AFR)

AF:

0.00112

AC:

AN:

29359

American (AMR)

AF:

0.00111

AC:

AN:

9901

Ashkenazi Jewish (ASJ)

AF:

0.00670

AC:

AN:

2539

East Asian (EAS)

AF:

0.000292

AC:

AN:

3426

South Asian (SAS)

AF:

0.00250

AC:

AN:

2404

European-Finnish (FIN)

AF:

0.00694

AC:

AN:

5330

Middle Eastern (MID)

AF:

0.00

AC:

AN:

208

European-Non Finnish (NFE)

AF:

0.00719

AC:

367

AN:

51075

Other (OTH)

AF:

0.00138

AC:

AN:

1448

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.00880

Hom.:

Bravo

AF:

0.00288

Asia WGS

AF:

0.00518

AC:

AN:

2521

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 17, 2023

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: COL4A5 c.1033-15delT alters a non-conserved nucleotide within a poly-T region located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0068 in 133794 control chromosomes in the gnomAD database, including 5 homozygotes. The observed variant frequency is approximately 1.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in COL4A5 causing Alport Syndrome 1, X-Linked Recessive phenotype (0.0046), strongly suggesting that the variant is benign. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:1

Feb 26, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

X-linked Alport syndrome

Benign:1

Dec 13, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.41

La Branchor

0.71

BranchPoint Hunter

6.0

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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