rs104886114

Positions:

• chrX-108591618-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_Moderate PM1 PM2 PP3_Strong PP5_Moderate

The NM_033380.3(COL4A5):​c.1397G>A​(p.Gly466Glu) 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. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.44

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 Pathogenic. Variant got 12 ACMG points.

• PS1: Transcript NM_033380.3 (COL4A5) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 0 uncertain in NM_033380.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant X-108591618-G-A is Pathogenic according to our data. Variant chrX-108591618-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 24406.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-108591618-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.1397G>A	p.Gly466Glu	missense_variant	21/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.1397G>A	p.Gly466Glu	missense_variant	21/53	1	NM_033380.3
COL4A5	ENST00000483338.1	c.221G>A	p.Gly74Glu	missense_variant	5/20	1
COL4A5	ENST00000361603.7	c.1397G>A	p.Gly466Glu	missense_variant	21/51	2		P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hematuria;C0239937:Microscopic hematuria Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 05, 2019

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS4_MOD,PM1,PM2,PP2,PP3. This variant was detected in heterozygous state. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.80
CADD	Uncertain	25
DANN	Benign	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Pathogenic	4.2	H;H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.4	D;D;.
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0020	D;D;.
Polyphen		0.053, 0.39	.;B;B
Vest4		0.99
MutPred		0.85		Gain of solvent accessibility (P = 0.0012);Gain of solvent accessibility (P = 0.0012);.;
MVP		0.99
MPC		0.39
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.93
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs104886114; hg19: chrX-107834848;