Genetic Variant COL4A5:c.1033-15dupT (chrX-108586590-A-AT) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_033380.3(COL4A5):c.1033-15dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00271 in 1,048,343 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., 4 hem., cov: 21)

Exomes 𝑓: 0.0030 ( 0 hom. 11 hem. )

Consequence

COL4A5
NM_033380.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000179 (19/106366) while in subpopulation AMR AF = 0.000909 (9/9899). AF 95% confidence interval is 0.000474. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
COL4A5	ENST00000328300.11 link	c.1033-25_1033-24insT	intron_variant	Intron 18 of 52	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1 link	c.-144-25_-144-24insT	intron_variant	Intron 2 of 19	1		ENSP00000495685.1
COL4A5	ENST00000361603.7 link	c.1033-25_1033-24insT	intron_variant	Intron 18 of 50	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes

AF:

0.000179

AC:

AN:

106333

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000102

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000910

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000582

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000979

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000979

AC:

131

AN:

133794

AF XY:

0.0000928

show subpopulations

Gnomad AFR exome

AF:

0.000784

Gnomad AMR exome

AF:

0.00151

Gnomad ASJ exome

AF:

0.00183

Gnomad EAS exome

AF:

0.00127

Gnomad FIN exome

AF:

0.000387

Gnomad NFE exome

AF:

0.000846

Gnomad OTH exome

AF:

0.00190

GnomAD4 exome

AF:

0.00300

AC:

2822

AN:

941977

Hom.:

Cov.:

AF XY:

0.0000369

AC XY:

AN XY:

298069

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00367

AC:

AN:

22350

American (AMR)

AF:

0.00177

AC:

AN:

31080

Ashkenazi Jewish (ASJ)

AF:

0.00208

AC:

AN:

16384

East Asian (EAS)

AF:

0.00172

AC:

AN:

26122

South Asian (SAS)

AF:

0.00156

AC:

AN:

46034

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

36393

Middle Eastern (MID)

AF:

0.00168

AC:

AN:

3572

European-Non Finnish (NFE)

AF:

0.00331

AC:

2384

AN:

720795

Other (OTH)

AF:

0.00270

AC:

106

AN:

39247

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.242

Heterozygous variant carriers

468

936

1405

1873

2341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

228

342

456

570

<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:

0.000179

AC:

AN:

106366

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

30140

show subpopulations

African (AFR)

AF:

0.000102

AC:

AN:

29358

American (AMR)

AF:

0.000909

AC:

AN:

9899

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2539

East Asian (EAS)

AF:

0.000584

AC:

AN:

3426

South Asian (SAS)

AF:

0.00

AC:

AN:

2404

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

208

European-Non Finnish (NFE)

AF:

0.0000979

AC:

AN:

51079

Other (OTH)

AF:

0.00

AC:

AN:

1448

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.0141

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.41

La Branchor

0.71

BranchPoint Hunter

6.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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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X-108586590-AT-ATT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over