dbSNP rs28465565: COL4A5:c.3553+42T>C (chrX-108666636-T-C) – ACMG Classification: Benign (-20 pts)

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.3553+42T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0314 in 1,064,300 control chromosomes in the GnomAD database, including 4,286 homozygotes. There are 8,964 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 2234 hom., 4092 hem., cov: 23)

Exomes 𝑓: 0.019 ( 2052 hom. 4872 hem. )

Consequence

COL4A5
NM_033380.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.271

Publications

2 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=-0.91).

BP6

Variant X-108666636-T-C is Benign according to our data. Variant chrX-108666636-T-C is described in ClinVar as Benign. ClinVar VariationId is 1267016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3 link	c.3553+42T>C		intron_variant	Intron 39 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.3553+42T>C		intron_variant	Intron 39 of 52	1	NM_033380.3	ENSP00000331902.7		P29400-2
COL4A5	ENST00000361603.7 link	c.3553+42T>C		intron_variant	Intron 39 of 50	2		ENSP00000354505.2		P29400-1

Frequencies

GnomAD3 genomes

AF:

0.134

AC:

14925

AN:

111550

Hom.:

2233

Cov.:

show subpopulations

Gnomad AFR

AF:

0.441

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0665

Gnomad ASJ

AF:

0.00265

Gnomad EAS

AF:

0.145

Gnomad SAS

AF:

0.0229

Gnomad FIN

AF:

0.000164

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00158

Gnomad OTH

AF:

0.108

GnomAD2 exomes

AF:

0.0522

AC:

6224

AN:

119139

AF XY:

0.0399

show subpopulations

Gnomad AFR exome

AF:

0.450

Gnomad AMR exome

AF:

0.0504

Gnomad ASJ exome

AF:

0.00411

Gnomad EAS exome

AF:

0.153

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00127

Gnomad OTH exome

AF:

0.0312

GnomAD4 exome

AF:

0.0193

AC:

18422

AN:

952695

Hom.:

2052

Cov.:

AF XY:

0.0185

AC XY:

4872

AN XY:

263657

show subpopulations

African (AFR)

AF:

0.448

AC:

10149

AN:

22671

American (AMR)

AF:

0.0549

AC:

1569

AN:

28600

Ashkenazi Jewish (ASJ)

AF:

0.00382

AC:

AN:

18067

East Asian (EAS)

AF:

0.121

AC:

3277

AN:

27091

South Asian (SAS)

AF:

0.0150

AC:

715

AN:

47674

European-Finnish (FIN)

AF:

0.000184

AC:

AN:

38052

Middle Eastern (MID)

AF:

0.0163

AC:

AN:

3746

European-Non Finnish (NFE)

AF:

0.000767

AC:

557

AN:

725776

Other (OTH)

AF:

0.0492

AC:

2018

AN:

41018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

465

931

1396

1862

2327

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

342

684

1026

1368

1710

<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:

0.134

AC:

14947

AN:

111605

Hom.:

2234

Cov.:

AF XY:

0.121

AC XY:

4092

AN XY:

33845

show subpopulations

African (AFR)

AF:

0.441

AC:

13425

AN:

30413

American (AMR)

AF:

0.0662

AC:

699

AN:

10556

Ashkenazi Jewish (ASJ)

AF:

0.00265

AC:

AN:

2644

East Asian (EAS)

AF:

0.144

AC:

510

AN:

3541

South Asian (SAS)

AF:

0.0223

AC:

AN:

2695

European-Finnish (FIN)

AF:

0.000164

AC:

AN:

6105

Middle Eastern (MID)

AF:

0.00

AC:

AN:

213

European-Non Finnish (NFE)

AF:

0.00158

AC:

AN:

53239

Other (OTH)

AF:

0.106

AC:

161

AN:

1514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

323

646

970

1293

1616

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

134

268

402

536

670

<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:

0.0696

Hom.:

679

Bravo

AF:

0.155

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.32

(source)

DANN

Benign

0.56

PhyloP100

-0.27

Mutation Taster

=100/0

polymorphism (auto)

(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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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