rs104886089

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_033380.3(COL4A5):c.1033-15del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00413 in 1,093,951 control chromosomes in the GnomAD database, including 15 homozygotes. There are 1,338 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.0045 ( 4 hom., 129 hem., cov: 21)

Exomes 𝑓: 0.0041 ( 11 hom. 1209 hem. )

Consequence

COL4A5
NM_033380.3 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.409

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant X-108586590-AT-A is Benign according to our data. Variant chrX-108586590-AT-A is described in ClinVar as [Likely_benign]. Clinvar id is 24358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108586590-AT-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00446 (474/106363) while in subpopulation NFE AF= 0.00719 (367/51075). AF 95% confidence interval is 0.00658. There are 4 homozygotes in gnomad4. There are 129 alleles in male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3 linkuse as main transcript	c.1033-15del		intron_variant		ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11 linkuse as main transcript	c.1033-15del	intron_variant	1	NM_033380.3	ENSP00000331902		P29400-2
COL4A5	ENST00000483338.1 linkuse as main transcript	c.-144-15del	intron_variant	1		ENSP00000495685
COL4A5	ENST00000361603.7 linkuse as main transcript	c.1033-15del	intron_variant	2		ENSP00000354505	P1	P29400-1

Frequencies

GnomAD3 genomes

AF:

0.00446

AC:

474

AN:

106330

Hom.:

Cov.:

AF XY:

0.00429

AC XY:

129

AN XY:

30088

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00670

Gnomad EAS

AF:

0.000291

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00694

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00718

Gnomad OTH

AF:

0.00140

GnomAD3 exomes

AF:

0.00681

AC:

911

AN:

133794

Hom.:

AF XY:

0.00698

AC XY:

301

AN XY:

43100

show subpopulations

Gnomad AFR exome

AF:

0.00206

Gnomad AMR exome

AF:

0.00291

Gnomad ASJ exome

AF:

0.00487

Gnomad EAS exome

AF:

0.00117

Gnomad SAS exome

AF:

0.00525

Gnomad FIN exome

AF:

0.0132

Gnomad NFE exome

AF:

0.00854

Gnomad OTH exome

AF:

0.0130

GnomAD4 exome

AF:

0.00410

AC:

4046

AN:

987588

Hom.:

Cov.:

AF XY:

0.00383

AC XY:

1209

AN XY:

315924

show subpopulations

Gnomad4 AFR exome

AF:

0.00119

Gnomad4 AMR exome

AF:

0.00228

Gnomad4 ASJ exome

AF:

0.00323

Gnomad4 EAS exome

AF:

0.000328

Gnomad4 SAS exome

AF:

0.00351

Gnomad4 FIN exome

AF:

0.0113

Gnomad4 NFE exome

AF:

0.00411

Gnomad4 OTH exome

AF:

0.00416

GnomAD4 genome

AF:

0.00446

AC:

474

AN:

106363

Hom.:

Cov.:

AF XY:

0.00428

AC XY:

129

AN XY:

30135

show subpopulations

Gnomad4 AFR

AF:

0.00112

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00670

Gnomad4 EAS

AF:

0.000292

Gnomad4 SAS

AF:

0.00250

Gnomad4 FIN

AF:

0.00694

Gnomad4 NFE

AF:

0.00719

Gnomad4 OTH

AF:

0.00138

Alfa

AF:

0.00880

Hom.:

Bravo

AF:

0.00288

Asia WGS

AF:

0.00518

AC:

AN:

2521

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Feb 17, 2023

Variant summary: COL4A5 c.1033-15delT alters a non-conserved nucleotide within a poly-T region located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0068 in 133794 control chromosomes in the gnomAD database, including 5 homozygotes. The observed variant frequency is approximately 1.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in COL4A5 causing Alport Syndrome 1, X-Linked Recessive phenotype (0.0046), strongly suggesting that the variant is benign. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 26, 2020

- -

X-linked Alport syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

La Branchor

0.71

BranchPoint Hunter

6.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over