rs104886349

Variant names:

• chrX-108559154-G-A
• rs104886349
• NM_033380.3:c.231+1G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-108559154-G-A
• chrX-108559154-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_033380.3(COL4A5):​c.231+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000167 in 1,194,790 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: COL4A5 NM_033380.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.09
• Publications: 2 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, Orphanet, Genomics England PanelApp, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.017730497 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-108559154-G-A is Pathogenic according to our data. Variant chrX-108559154-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 24248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033380.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	NM_033380.3	MANE Select	c.231+1G>A		splice_donor intron	N/A	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.231+1G>A		splice_donor intron	N/A	NP_000486.1	P29400-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	ENST00000328300.11	TSL:1 MANE Select	c.231+1G>A		splice_donor intron	N/A	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000949143.1		c.231+1G>A		splice_donor intron	N/A	ENSP00000619202.1
	COL4A5	ENST00000361603.7	TSL:2	c.231+1G>A		splice_donor intron	N/A	ENSP00000354505.2	P29400-1

Frequencies

GnomAD3 genomes AF: 0.00000891 AC: 1 AN: 112218 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.24e-7 AC: 1 AN: 1082572 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 348686

African (AFR) AF: 0.00 AC: 0 AN: 26104

American (AMR) AF: 0.00 AC: 0 AN: 35135

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19276

East Asian (EAS) AF: 0.00 AC: 0 AN: 30164

South Asian (SAS) AF: 0.00 AC: 0 AN: 53781

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40475

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4084

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 827998

Other (OTH) AF: 0.00 AC: 0 AN: 45555

GnomAD4 genome AF: 0.00000891 AC: 1 AN: 112218 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34394

African (AFR) AF: 0.0000323 AC: 1 AN: 30934

American (AMR) AF: 0.00 AC: 0 AN: 10554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3558

South Asian (SAS) AF: 0.00 AC: 0 AN: 2670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6139

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53270

Other (OTH) AF: 0.00 AC: 0 AN: 1516

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	28
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		8.1
GERP RS		5.6
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.96		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs104886349; hg19: chrX-107802384;