NM_033380.3:c.1498G>C

Variant names:

• chrX-108595583-G-C
• rs281874670
• NM_033380.3:c.1498G>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_033380.3(COL4A5):​c.1498G>C​(p.Gly500Arg) variant causes a missense 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G500C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.00
• 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: 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 13 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_033380.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-108595584-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2627801.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-108595583-G-C is Pathogenic according to our data. Variant chrX-108595583-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 24419.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.1498G>C	p.Gly500Arg	missense	Exon 22 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.1498G>C	p.Gly500Arg	missense	Exon 22 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.1498G>C	p.Gly500Arg	missense	Exon 22 of 53	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000483338.1	TSL:1	c.322G>C	p.Gly108Arg	missense	Exon 6 of 20	ENSP00000495685.1	Q49AM6
	COL4A5	ENST00000949143.1		c.1498G>C	p.Gly500Arg	missense	Exon 22 of 51	ENSP00000619202.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

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
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		9.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.94		Gain of solvent accessibility (P = 0.0037)
MVP		1.0
MPC		0.36
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs281874670; hg19: chrX-107838813;