rs104886089

chrX-108586590-AT-AchrX-108586590-AT-ATTchrX-108586590-AT-ATTTTTTT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

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 (★★).

• 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.409

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.1033-15del		intron_variant		ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.1033-15del		intron_variant		1	NM_033380.3
COL4A5	ENST00000483338.1	c.-144-15del		intron_variant		1
COL4A5	ENST00000361603.7	c.1033-15del		intron_variant		2		P1

Frequencies

GnomAD3 genomes AF: 0.00446 AC: 474 AN: 106330 Hom.: 4 Cov.: 21 AF XY: 0.00429 AC XY: 129 AN XY: 30088

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.: 5 AF XY: 0.00698 AC XY: 301 AN XY: 43100

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.: 11 Cov.: 26 AF XY: 0.00383 AC XY: 1209 AN XY: 315924

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.: 4 Cov.: 21 AF XY: 0.00428 AC XY: 129 AN XY: 30135

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.: 0

Bravo AF: 0.00288

Asia WGS AF: 0.00518 AC: 13 AN: 2521

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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

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

Other links and lift over

dbSNP: rs104886089; hg19: chrX-107829820;