rs28465565

Positions:

• chrX-108666636-T-C
• chrX-108666636-T-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.3553+42T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0314 in 1,064,300 control chromosomes in the GnomAD database, including 4,286 homozygotes. There are 8,964 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2234 hom., 4092 hem., cov: 23)
  • Exomes 𝑓: 0.019 (2052 hom. 4872 hem.)
• Consequence: COL4A5 NM_033380.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.271

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=-0.91).
• BP6: Variant X-108666636-T-C is Benign according to our data. Variant chrX-108666636-T-C is described in ClinVar as [Benign]. Clinvar id is 1267016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108666636-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.3553+42T>C		intron_variant		ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.3553+42T>C		intron_variant		1	NM_033380.3
COL4A5	ENST00000361603.7	c.3553+42T>C		intron_variant		2		P1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 14925 AN: 111550 Hom.: 2233 Cov.: 23 AF XY: 0.120 AC XY: 4070 AN XY: 33780

Gnomad AFR AF: 0.441

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0665

Gnomad ASJ AF: 0.00265

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.0229

Gnomad FIN AF: 0.000164

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00158

Gnomad OTH AF: 0.108

GnomAD3 exomes AF: 0.0522 AC: 6224 AN: 119139 Hom.: 675 AF XY: 0.0399 AC XY: 1611 AN XY: 40339

Gnomad AFR exome AF: 0.450

Gnomad AMR exome AF: 0.0504

Gnomad ASJ exome AF: 0.00411

Gnomad EAS exome AF: 0.153

Gnomad SAS exome AF: 0.0166

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.0312

GnomAD4 exome AF: 0.0193 AC: 18422 AN: 952695 Hom.: 2052 Cov.: 19 AF XY: 0.0185 AC XY: 4872 AN XY: 263657

Gnomad4 AFR exome AF: 0.448

Gnomad4 AMR exome AF: 0.0549

Gnomad4 ASJ exome AF: 0.00382

Gnomad4 EAS exome AF: 0.121

Gnomad4 SAS exome AF: 0.0150

Gnomad4 FIN exome AF: 0.000184

Gnomad4 NFE exome AF: 0.000767

Gnomad4 OTH exome AF: 0.0492

GnomAD4 genome AF: 0.134 AC: 14947 AN: 111605 Hom.: 2234 Cov.: 23 AF XY: 0.121 AC XY: 4092 AN XY: 33845

Gnomad4 AFR AF: 0.441

Gnomad4 AMR AF: 0.0662

Gnomad4 ASJ AF: 0.00265

Gnomad4 EAS AF: 0.144

Gnomad4 SAS AF: 0.0223

Gnomad4 FIN AF: 0.000164

Gnomad4 NFE AF: 0.00158

Gnomad4 OTH AF: 0.106

Alfa AF: 0.0696 Hom.: 679

Bravo AF: 0.155

ClinVar

Significance: Benign

Submissions summary: Benign:2

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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.32
DANN	Benign	0.56

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

LitVar

Other links and lift over

dbSNP: rs28465565; hg19: chrX-107909866;