X-108606891-A-T

Variant names:

• chrX-108606891-A-T
• rs281874691
• NM_033380.3:c.2394A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_033380.3(COL4A5):​c.2394A>T​(p.Lys798Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K798E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 missense, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.79
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 1 uncertain in NM_033380.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 538 curated pathogenic missense variants (we use a threshold of 10). The gene has 138 curated benign missense variants. Gene score misZ: 2.4995 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked Alport syndrome, Alport syndrome.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.2394A>T	p.Lys798Asn	missense splice_region	Exon 29 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.2394A>T	p.Lys798Asn	missense splice_region	Exon 29 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.2394A>T	p.Lys798Asn	missense splice_region	Exon 29 of 53	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000483338.1	TSL:1	c.1218A>T	p.Lys406Asn	missense splice_region	Exon 13 of 20	ENSP00000495685.1	Q49AM6
	COL4A5	ENST00000949143.1		c.2394A>T	p.Lys798Asn	missense splice_region	Exon 29 of 51	ENSP00000619202.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		8.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.044	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.47		Loss of ubiquitination at K798 (P = 0.0051)
MVP		0.93
MPC		0.35
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.89
gMVP		0.84
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.57		Position offset: 1

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

Other links and lift over

dbSNP: rs281874691; hg19: chrX-107850121;