chrX-108601867-A-G

Variant names:

• chrX-108601867-A-G
• rs104886341
• NM_033380.3:c.2042-18A>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_033380.3(COL4A5):​c.2042-18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: COL4A5 NM_033380.3 intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.49
• Publications: 1 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: Uncertain_significance. The variant received 5 ACMG points.

• 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-108601867-A-G is Pathogenic according to our data. Variant chrX-108601867-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 3255205.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	NM_033380.3	MANE Select	c.2042-18A>G		intron	N/A	NP_203699.1
	COL4A5	NM_000495.5		c.2042-18A>G		intron	N/A	NP_000486.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	ENST00000328300.11	TSL:1 MANE Select	c.2042-18A>G		intron	N/A	ENSP00000331902.7
	COL4A5	ENST00000483338.1	TSL:1	c.866-18A>G		intron	N/A	ENSP00000495685.1
	COL4A5	ENST00000949143.1		c.2042-18A>G		intron	N/A	ENSP00000619202.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 864454 Hom.: 0 Cov.: 14 AF XY: 0.00 AC XY: 0 AN XY: 243742

African (AFR) AF: 0.00 AC: 0 AN: 20634

American (AMR) AF: 0.00 AC: 0 AN: 27987

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17346

East Asian (EAS) AF: 0.00 AC: 0 AN: 26581

South Asian (SAS) AF: 0.00 AC: 0 AN: 45983

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37555

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3477

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 646960

Other (OTH) AF: 0.00 AC: 0 AN: 37931

GnomAD4 genome Cov.: 22

Alfa AF: 0.00108 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	23
DANN	Benign	0.79
PhyloP100		1.5
BranchPoint Hunter		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=36/64	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.58		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.58		Position offset: 1

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

Other links and lift over

dbSNP: rs104886341; hg19: chrX-107845097;