rs6622333

Positions:

• chrX-108575993-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000328300.11(COL4A5):​c.609+21T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 1,064,430 control chromosomes in the GnomAD database, including 24,049 homozygotes. There are 72,216 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (2111 hom., 6467 hem., cov: 22)
  • Exomes 𝑓: 0.23 (21938 hom. 65749 hem.)
• Consequence: COL4A5 ENST00000328300.11 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.116

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant X-108575993-T-C is Benign according to our data. Variant chrX-108575993-T-C is described in ClinVar as [Benign]. Clinvar id is 24296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108575993-T-C is described in Lovd as [Benign]. Variant chrX-108575993-T-C is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.609+21T>C		intron_variant		ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.609+21T>C		intron_variant		1	NM_033380.3	ENSP00000331902
COL4A5	ENST00000361603.7	c.609+21T>C		intron_variant		2		ENSP00000354505	P1

Frequencies

GnomAD3 genomes AF: 0.196 AC: 21656 AN: 110406 Hom.: 2111 Cov.: 22 AF XY: 0.198 AC XY: 6454 AN XY: 32658

Gnomad AFR AF: 0.0638

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.437

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.571

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.195

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.218

GnomAD3 exomes AF: 0.300 AC: 45808 AN: 152783 Hom.: 6838 AF XY: 0.295 AC XY: 14121 AN XY: 47831

Gnomad AFR exome AF: 0.0591

Gnomad AMR exome AF: 0.610

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.562

Gnomad SAS exome AF: 0.375

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.198

Gnomad OTH exome AF: 0.270

GnomAD4 exome AF: 0.230 AC: 219441 AN: 953977 Hom.: 21938 Cov.: 18 AF XY: 0.248 AC XY: 65749 AN XY: 265611

Gnomad4 AFR exome AF: 0.0587

Gnomad4 AMR exome AF: 0.586

Gnomad4 ASJ exome AF: 0.178

Gnomad4 EAS exome AF: 0.640

Gnomad4 SAS exome AF: 0.377

Gnomad4 FIN exome AF: 0.148

Gnomad4 NFE exome AF: 0.198

Gnomad4 OTH exome AF: 0.230

GnomAD4 genome AF: 0.196 AC: 21666 AN: 110453 Hom.: 2111 Cov.: 22 AF XY: 0.198 AC XY: 6467 AN XY: 32715

Gnomad4 AFR AF: 0.0639

Gnomad4 AMR AF: 0.437

Gnomad4 ASJ AF: 0.170

Gnomad4 EAS AF: 0.571

Gnomad4 SAS AF: 0.372

Gnomad4 FIN AF: 0.134

Gnomad4 NFE AF: 0.198

Gnomad4 OTH AF: 0.214

Alfa AF: 0.187 Hom.: 2138

Bravo AF: 0.218

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

X-linked Alport syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 25, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 15, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 58% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 54. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.4
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6622333; hg19: chrX-107819223;