NM_033380.3:c.3148C>G

Variant names:

• chrX-108626251-C-G
• rs143945573
• NM_033380.3:c.3148C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_033380.3(COL4A5):​c.3148C>G​(p.Pro1050Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1050S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 3.51
• Publications: 2 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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.3148C>G	p.Pro1050Ala	missense_variant	Exon 36 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.3148C>G	p.Pro1050Ala	missense_variant	Exon 36 of 53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.1972C>G	p.Pro658Ala	missense_variant	Exon 20 of 20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.3148C>G	p.Pro1050Ala	missense_variant	Exon 36 of 51	2		ENSP00000354505.2
COL4A5	ENST00000505728.1	c.379C>G	p.Pro127Ala	missense_variant	Exon 4 of 5	3		ENSP00000424137.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

X-linked Alport syndrome Uncertain:1

-

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.83	.;D;D
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	D;D;T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	1.9	L;L;.
PhyloP100		3.5
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.3	D;D;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.014	D;D;.
Sift4G	Benign	0.20	T;T;.
Polyphen		0.012, 0.0050	.;B;B
Vest4		0.34
MutPred		0.47		Loss of relative solvent accessibility (P = 0.1807);Loss of relative solvent accessibility (P = 0.1807);.;
MVP		0.81
MPC		0.29
ClinPred		0.58	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.29
Mutation Taster		=85/15	polymorphism

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: rs143945573; hg19: chrX-107869481;