Genetic Variant COL4A5:n.267C>T (chrX-108440110-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_033380.3(COL4A5):c.-16C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,191,816 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 76 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., 5 hem., cov: 21)

Exomes 𝑓: 0.00021 ( 0 hom. 71 hem. )

Consequence

COL4A5
NM_033380.3 5_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.09

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

BS2

High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3 link	c.-16C>T	5_prime_UTR_variant	Exon 1 of 53	ENST00000328300.11	NP_203699.1	P29400-2Q49AM6A7MBN3
COL4A5	NM_000495.5 link	c.-16C>T	5_prime_UTR_variant	Exon 1 of 51		NP_000486.1	P29400-1Q49AM6A7MBN3
COL4A5	XM_047441810.1 link	c.-392C>T	5_prime_UTR_variant	Exon 1 of 54		XP_047297766.1
COL4A5	XM_047441811.1 link	c.-16C>T	5_prime_UTR_variant	Exon 1 of 42		XP_047297767.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11 link	c.-16C>T		5_prime_UTR_variant	Exon 1 of 53	1	NM_033380.3	ENSP00000331902.7		P29400-2

Frequencies

GnomAD3 genomes

AF:

0.000274

AC:

AN:

109341

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00496

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000334

AC:

AN:

176879

AF XY:

0.000355

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00448

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000267

Gnomad OTH exome

AF:

0.00113

GnomAD4 exome

AF:

0.000205

AC:

222

AN:

1082475

Hom.:

Cov.:

AF XY:

0.000203

AC XY:

AN XY:

349805

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26103

American (AMR)

AF:

0.00

AC:

AN:

35055

Ashkenazi Jewish (ASJ)

AF:

0.00488

AC:

AN:

19270

East Asian (EAS)

AF:

0.00

AC:

AN:

30126

South Asian (SAS)

AF:

0.00

AC:

AN:

53289

European-Finnish (FIN)

AF:

0.0000498

AC:

AN:

40197

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4057

European-Non Finnish (NFE)

AF:

0.000133

AC:

110

AN:

828777

Other (OTH)

AF:

0.000351

AC:

AN:

45601

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000274

AC:

AN:

109341

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

AN XY:

31623

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30005

American (AMR)

AF:

0.00

AC:

AN:

10192

Ashkenazi Jewish (ASJ)

AF:

0.00496

AC:

AN:

2622

East Asian (EAS)

AF:

0.00

AC:

AN:

3463

South Asian (SAS)

AF:

0.00

AC:

AN:

2439

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5660

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

52585

Other (OTH)

AF:

0.00

AC:

AN:

1457

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000763

Hom.:

Bravo

AF:

0.000196

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 08, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

1.1

PromoterAI

0.035

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=300/0

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-108440110-C-T

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