X-108615029-G-T

Variant names:

• chrX-108615029-G-T
• rs1556418297
• NM_033380.3:c.2509+5G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_033380.3(COL4A5):​c.2509+5G>T variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000294 in 1,021,882 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000029 (0 hom. 0 hem.)
• Consequence: COL4A5 NM_033380.3 splice_region, intron
• Scores: Splicing: ADA: 0.9986
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.48
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.2509+5G>T		splice_region_variant, intron_variant	Intron 30 of 52	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.2509+5G>T		splice_region_variant, intron_variant	Intron 30 of 52	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.1333+5G>T		splice_region_variant, intron_variant	Intron 14 of 19	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.2509+5G>T		splice_region_variant, intron_variant	Intron 30 of 50	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000294 AC: 3 AN: 1021882 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 298438

African (AFR) AF: 0.00 AC: 0 AN: 25053

American (AMR) AF: 0.00 AC: 0 AN: 35086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18891

East Asian (EAS) AF: 0.00 AC: 0 AN: 29913

South Asian (SAS) AF: 0.00 AC: 0 AN: 52181

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40443

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3953

European-Non Finnish (NFE) AF: 0.00000388 AC: 3 AN: 772746

Other (OTH) AF: 0.00 AC: 0 AN: 43616

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	23
DANN	Benign	0.94
PhyloP100		4.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.22		Position offset: -5

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

Other links and lift over

dbSNP: rs1556418297; hg19: chrX-107858259;