rs104886299

Variant names:

• chrX-108694909-T-G
• rs104886299
• NM_033380.3:c.4809T>G

Your query was ambiguous. Multiple possible variants found:

• chrX-108694909-T-G
• chrX-108694909-T-A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1 PM2 PP3_Moderate PP5_Moderate

The NM_033380.3(COL4A5):​c.4809T>G​(p.Tyr1603*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000935 in 1,069,928 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. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.3e-7 (0 hom. 0 hem.)
• Consequence: COL4A5 NM_033380.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.25
• 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: G2P, ClinGen
• X-linked Alport syndrome

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

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-108694909-T-G is Pathogenic according to our data. Variant chrX-108694909-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1344647.Status of the report is criteria_provided_single_submitter, 1 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.4809T>G	p.Tyr1603*	stop_gained	Exon 51 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.4791T>G	p.Tyr1597*	stop_gained	Exon 49 of 51	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.4809T>G	p.Tyr1603*	stop_gained	Exon 51 of 53	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000949143.1		c.4803T>G	p.Tyr1601*	stop_gained	Exon 49 of 51	ENSP00000619202.1
	COL4A5	ENST00000361603.7	TSL:2	c.4791T>G	p.Tyr1597*	stop_gained	Exon 49 of 51	ENSP00000354505.2	P29400-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.35e-7 AC: 1 AN: 1069928 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 337206

African (AFR) AF: 0.00 AC: 0 AN: 25868

American (AMR) AF: 0.00 AC: 0 AN: 35161

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19205

East Asian (EAS) AF: 0.00 AC: 0 AN: 30089

South Asian (SAS) AF: 0.00 AC: 0 AN: 53500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4030

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 816367

Other (OTH) AF: 0.00 AC: 0 AN: 45188

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Alport syndrome (1)
1	-	-	X-linked Alport syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	41
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.89	D
PhyloP100		1.3
Vest4		0.92
GERP RS		5.6
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.83		Position offset: -5
DS_DL_spliceai		0.38		Position offset: 12

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

Other links and lift over

dbSNP: rs104886299; hg19: chrX-107938139;