rs1006269

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_033380.3(COL4A5):c.2768-11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,207,751 control chromosomes in the GnomAD database, including 8,060 homozygotes. There are 50,294 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 637 hom., 3543 hem., cov: 23)

Exomes 𝑓: 0.13 ( 7423 hom. 46751 hem. )

Consequence

COL4A5
NM_033380.3 intron

Scores

Splicing: ADA: 0.00003877

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.145

Publications

13 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant X-108622665-A-G is Benign according to our data. Variant chrX-108622665-A-G is described in ClinVar as Benign. ClinVar VariationId is 24563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3 link	c.2768-11A>G		intron_variant	Intron 32 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.2768-11A>G	intron_variant	Intron 32 of 52	1	NM_033380.3	ENSP00000331902.7	P29400-2
COL4A5	ENST00000483338.1 link	c.1592-11A>G	intron_variant	Intron 16 of 19	1		ENSP00000495685.1	Q49AM6
COL4A5	ENST00000361603.7 link	c.2768-11A>G	intron_variant	Intron 32 of 50	2		ENSP00000354505.2	P29400-1
COL4A5	ENST00000505728.1 link	c.-13A>G	upstream_gene_variant		3		ENSP00000424137.1	H0Y9H0

Frequencies

GnomAD3 genomes

AF:

0.101

AC:

11326

AN:

111943

Hom.:

638

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0173

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.222

Gnomad ASJ

AF:

0.0763

Gnomad EAS

AF:

0.326

Gnomad SAS

AF:

0.236

Gnomad FIN

AF:

0.0696

Gnomad MID

AF:

0.0763

Gnomad NFE

AF:

0.111

Gnomad OTH

AF:

0.0979

GnomAD2 exomes

AF:

0.161

AC:

29492

AN:

182713

AF XY:

0.159

show subpopulations

Gnomad AFR exome

AF:

0.0153

Gnomad AMR exome

AF:

0.326

Gnomad ASJ exome

AF:

0.0744

Gnomad EAS exome

AF:

0.323

Gnomad FIN exome

AF:

0.0792

Gnomad NFE exome

AF:

0.107

Gnomad OTH exome

AF:

0.138

GnomAD4 exome

AF:

0.126

AC:

138272

AN:

1095759

Hom.:

7423

Cov.:

AF XY:

0.129

AC XY:

46751

AN XY:

361757

show subpopulations

African (AFR)

AF:

0.0147

AC:

388

AN:

26354

American (AMR)

AF:

0.313

AC:

11002

AN:

35161

Ashkenazi Jewish (ASJ)

AF:

0.0754

AC:

1460

AN:

19361

East Asian (EAS)

AF:

0.360

AC:

10879

AN:

30182

South Asian (SAS)

AF:

0.246

AC:

13316

AN:

54068

European-Finnish (FIN)

AF:

0.0819

AC:

3319

AN:

40514

Middle Eastern (MID)

AF:

0.0665

AC:

262

AN:

3940

European-Non Finnish (NFE)

AF:

0.110

AC:

92023

AN:

840200

Other (OTH)

AF:

0.122

AC:

5623

AN:

45979

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

3651

7301

10952

14602

18253

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3686

7372

11058

14744

18430

<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:

0.101

AC:

11324

AN:

111992

Hom.:

637

Cov.:

AF XY:

0.104

AC XY:

3543

AN XY:

34190

show subpopulations

African (AFR)

AF:

0.0173

AC:

535

AN:

30953

American (AMR)

AF:

0.222

AC:

2352

AN:

10578

Ashkenazi Jewish (ASJ)

AF:

0.0763

AC:

202

AN:

2647

East Asian (EAS)

AF:

0.327

AC:

1145

AN:

3501

South Asian (SAS)

AF:

0.236

AC:

630

AN:

2665

European-Finnish (FIN)

AF:

0.0696

AC:

427

AN:

6132

Middle Eastern (MID)

AF:

0.0698

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.111

AC:

5869

AN:

53086

Other (OTH)

AF:

0.0954

AC:

146

AN:

1531

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

337

674

1012

1349

1686

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

264

396

528

660

<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:

0.111

Hom.:

5134

Bravo

AF:

0.109

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 37% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 34. Only high quality variants are reported. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 17, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 25, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.2768-11A>G in intron 32A of COL4A5: This variant is not expected to have clini cal significance because it has been identified in 32.6% (8823/27099) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinsti tute.org/; dbSNP rs1006269). -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

X-linked Alport syndrome

Benign:2

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 04, 2021

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

BayesDel_noAF

Benign

-0.81

CADD

Benign

4.9

(source)

DANN

Benign

0.84

PhyloP100

-0.14

PromoterAI

0.024

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000039

dbscSNV1_RF

Benign

0.0080

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over