rs1006269

chrX-108622665-A-G

Variant summary

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

The NM_033380.3(COL4A5):c.2768-11A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,207,751 control chromosomes in the GnomAD database, including 8,060 homozygotes. There are 50,294 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (637 hom., 3543 hem., cov: 23)
  • Exomes 𝑓: 0.13 (7423 hom. 46751 hem.)
• Consequence: COL4A5 NM_033380.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003877
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.145

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=-0.81).
• BP6: Variant X-108622665-A-G is Benign according to our data. Variant chrX-108622665-A-G is described in ClinVar as [Benign]. Clinvar id is 24563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108622665-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.2768-11A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.2768-11A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_033380.3
COL4A5	ENST00000483338.1	c.1592-11A>G		splice_polypyrimidine_tract_variant, intron_variant		1
COL4A5	ENST00000361603.7	c.2768-11A>G		splice_polypyrimidine_tract_variant, intron_variant		2		P1
COL4A5	ENST00000505728.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.101 AC: 11326 AN: 111943 Hom.: 638 Cov.: 23 AF XY: 0.104 AC XY: 3539 AN XY: 34131

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.0763

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.0696

Gnomad MID AF: 0.0763

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.0979

GnomAD3 exomes AF: 0.161 AC: 29492 AN: 182713 Hom.: 2311 AF XY: 0.159 AC XY: 10721 AN XY: 67427

Gnomad AFR exome AF: 0.0153

Gnomad AMR exome AF: 0.326

Gnomad ASJ exome AF: 0.0744

Gnomad EAS exome AF: 0.323

Gnomad SAS exome AF: 0.248

Gnomad FIN exome AF: 0.0792

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.138

GnomAD4 exome AF: 0.126 AC: 138272 AN: 1095759 Hom.: 7423 Cov.: 30 AF XY: 0.129 AC XY: 46751 AN XY: 361757

Gnomad4 AFR exome AF: 0.0147

Gnomad4 AMR exome AF: 0.313

Gnomad4 ASJ exome AF: 0.0754

Gnomad4 EAS exome AF: 0.360

Gnomad4 SAS exome AF: 0.246

Gnomad4 FIN exome AF: 0.0819

Gnomad4 NFE exome AF: 0.110

Gnomad4 OTH exome AF: 0.122

GnomAD4 genome AF: 0.101 AC: 11324 AN: 111992 Hom.: 637 Cov.: 23 AF XY: 0.104 AC XY: 3543 AN XY: 34190

Gnomad4 AFR AF: 0.0173

Gnomad4 AMR AF: 0.222

Gnomad4 ASJ AF: 0.0763

Gnomad4 EAS AF: 0.327

Gnomad4 SAS AF: 0.236

Gnomad4 FIN AF: 0.0696

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.0954

Alfa AF: 0.113 Hom.: 3810

Bravo AF: 0.109

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 25, 2017	c.2768-11A>G in intron 32A of COL4A5: This variant is not expected to have clini cal significance because it has been identified in 32.6% (8823/27099) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinsti tute.org/; dbSNP rs1006269). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

X-linked Alport syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 04, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	4.9
Dann	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000039
dbscSNV1_RF	Benign	0.0080
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

LitVar

Other links and lift over

dbSNP: rs1006269; hg19: chrX-107865895; COSMIC: COSV60362795; COSMIC: COSV60362795;