rs143945573

chrX-108626251-C-GchrX-108626251-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a compositionally_biased_region Pro residues (size 14) in uniprot entity CO4A5_HUMAN there are 8 pathogenic changes around while only 2 benign (80%) in NM_033380.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.3148C>G	p.Pro1050Ala	missense_variant	36/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.3148C>G	p.Pro1050Ala	missense_variant	36/53	1	NM_033380.3
COL4A5	ENST00000483338.1	c.1972C>G	p.Pro658Ala	missense_variant	20/20	1
COL4A5	ENST00000361603.7	c.3148C>G	p.Pro1050Ala	missense_variant	36/51	2		P1
COL4A5	ENST00000505728.1	c.382C>G	p.Pro128Ala	missense_variant	4/5	3

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

Uncertain significance, no assertion criteria provided

clinical testing

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

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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
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;.
MutationTaster	Benign	1.0	D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs143945573; hg19: chrX-107869481;