chrX-108575993-T-C

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.609+21T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 1,064,430 control chromosomes in the GnomAD database, including 24,049 homozygotes. There are 72,216 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 2111 hom., 6467 hem., cov: 22)

Exomes 𝑓: 0.23 ( 21938 hom. 65749 hem. )

Consequence

COL4A5
NM_033380.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.116

Publications

9 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=-0.78).

BP6

Variant X-108575993-T-C is Benign according to our data. Variant chrX-108575993-T-C is described in ClinVar as Benign. ClinVar VariationId is 24296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3 link	c.609+21T>C		intron_variant	Intron 10 of 52	ENST00000328300.11	NP_203699.1	P29400-2Q49AM6A7MBN3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11 link	c.609+21T>C		intron_variant	Intron 10 of 52	1	NM_033380.3	ENSP00000331902.7		P29400-2
COL4A5	ENST00000361603.7 link	c.609+21T>C		intron_variant	Intron 10 of 50	2		ENSP00000354505.2		P29400-1

Frequencies

GnomAD3 genomes

AF:

0.196

AC:

21656

AN:

110406

Hom.:

2111

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0638

Gnomad AMI

AF:

0.356

Gnomad AMR

AF:

0.437

Gnomad ASJ

AF:

0.170

Gnomad EAS

AF:

0.571

Gnomad SAS

AF:

0.370

Gnomad FIN

AF:

0.134

Gnomad MID

AF:

0.195

Gnomad NFE

AF:

0.198

Gnomad OTH

AF:

0.218

GnomAD2 exomes

AF:

0.300

AC:

45808

AN:

152783

AF XY:

0.295

show subpopulations

Gnomad AFR exome

AF:

0.0591

Gnomad AMR exome

AF:

0.610

Gnomad ASJ exome

AF:

0.179

Gnomad EAS exome

AF:

0.562

Gnomad FIN exome

AF:

0.141

Gnomad NFE exome

AF:

0.198

Gnomad OTH exome

AF:

0.270

GnomAD4 exome

AF:

0.230

AC:

219441

AN:

953977

Hom.:

21938

Cov.:

AF XY:

0.248

AC XY:

65749

AN XY:

265611

show subpopulations

African (AFR)

AF:

0.0587

AC:

1383

AN:

23554

American (AMR)

AF:

0.586

AC:

19901

AN:

33984

Ashkenazi Jewish (ASJ)

AF:

0.178

AC:

3266

AN:

18305

East Asian (EAS)

AF:

0.640

AC:

18327

AN:

28643

South Asian (SAS)

AF:

0.377

AC:

18492

AN:

49091

European-Finnish (FIN)

AF:

0.148

AC:

5835

AN:

39342

Middle Eastern (MID)

AF:

0.192

AC:

735

AN:

3821

European-Non Finnish (NFE)

AF:

0.198

AC:

142059

AN:

716178

Other (OTH)

AF:

0.230

AC:

9443

AN:

41059

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

4455

8911

13366

17822

22277

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5214

10428

15642

20856

26070

<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:

0.196

AC:

21666

AN:

110453

Hom.:

2111

Cov.:

AF XY:

0.198

AC XY:

6467

AN XY:

32715

show subpopulations

African (AFR)

AF:

0.0639

AC:

1945

AN:

30459

American (AMR)

AF:

0.437

AC:

4489

AN:

10263

Ashkenazi Jewish (ASJ)

AF:

0.170

AC:

448

AN:

2640

East Asian (EAS)

AF:

0.571

AC:

1981

AN:

3470

South Asian (SAS)

AF:

0.372

AC:

952

AN:

2562

European-Finnish (FIN)

AF:

0.134

AC:

778

AN:

5817

Middle Eastern (MID)

AF:

0.200

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.198

AC:

10471

AN:

52860

Other (OTH)

AF:

0.214

AC:

321

AN:

1498

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

565

1130

1695

2260

2825

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

228

456

684

912

1140

<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:

0.176

Hom.:

3959

Bravo

AF:

0.218

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

X-linked Alport syndrome

Benign:2

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 25, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

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 58% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 54. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

2.4

(source)

DANN

Benign

0.83

PhyloP100

0.12

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over