rs104886110

Positions:

• chrX-108591160-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1_Moderate PM1 PM2 PP3_Strong PP5

The NM_033380.3(COL4A5):​c.1268G>A​(p.Gly423Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,399 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in Lovd as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.49

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 11 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 compositionally_biased_region Pro residues (size 47) in uniprot entity CO4A5_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_033380.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant X-108591160-G-A is Pathogenic according to our data. Variant chrX-108591160-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.1268G>A	p.Gly423Glu	missense_variant	20/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.1268G>A	p.Gly423Glu	missense_variant	20/53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.92G>A	p.Gly31Glu	missense_variant	4/20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.1268G>A	p.Gly423Glu	missense_variant	20/51	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096399 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 362643

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.77
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	.;D;D
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H;H;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.9	D;D;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0030	D;D;.
Sift4G	Uncertain	0.0020	D;D;.
Polyphen		0.58, 0.78	.;P;P
Vest4		0.99
MutPred		0.99		Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);.;
MVP		1.0
MPC		0.39
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.99
gMVP		1.0

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: rs104886110; hg19: chrX-107834390;