X-108583309-A-G

Variant names:

• chrX-108583309-A-G
• rs10521520
• NM_033380.3:c.990+372A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033380.3(COL4A5):​c.990+372A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 111,112 control chromosomes in the GnomAD database, including 2,816 homozygotes. There are 8,194 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.25 (2816 hom., 8194 hem., cov: 23)
• Consequence: COL4A5 NM_033380.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.663
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Alport syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen, G2P
• X-linked Alport syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.990+372A>G		intron_variant	Intron 17 of 52	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.990+372A>G		intron_variant	Intron 17 of 52	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.-187+372A>G		intron_variant	Intron 1 of 19	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.990+372A>G		intron_variant	Intron 17 of 50	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes AF: 0.247 AC: 27405 AN: 111057 Hom.: 2813 Cov.: 23

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.460

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.568

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.246

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.247 AC: 27438 AN: 111112 Hom.: 2816 Cov.: 23 AF XY: 0.245 AC XY: 8194 AN XY: 33412

African (AFR) AF: 0.212 AC: 6505 AN: 30630

American (AMR) AF: 0.461 AC: 4816 AN: 10453

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 465 AN: 2628

East Asian (EAS) AF: 0.569 AC: 1973 AN: 3469

South Asian (SAS) AF: 0.373 AC: 1001 AN: 2686

European-Finnish (FIN) AF: 0.135 AC: 814 AN: 6017

Middle Eastern (MID) AF: 0.215 AC: 46 AN: 214

European-Non Finnish (NFE) AF: 0.213 AC: 11244 AN: 52836

Other (OTH) AF: 0.242 AC: 365 AN: 1506

Alfa AF: 0.221 Hom.: 1361

Bravo AF: 0.275

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.3
DANN	Benign	0.50
PhyloP100		0.66
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10521520; hg19: chrX-107826539;