rs104886140

Positions:

• chrX-108598748-G-C
• chrX-108598748-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_033380.3(COL4A5):​c.1826G>C​(p.Gly609Ala) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G609C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.31

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.

• PM1: In a compositionally_biased_region Pro residues (size 22) in uniprot entity CO4A5_HUMAN there are 17 pathogenic changes around while only 6 benign (74%) 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant X-108598748-G-C is Pathogenic according to our data. Variant chrX-108598748-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 974424.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.1826G>C	p.Gly609Ala	missense_variant	25/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.1826G>C	p.Gly609Ala	missense_variant	25/53	1	NM_033380.3
COL4A5	ENST00000483338.1	c.650G>C	p.Gly217Ala	missense_variant	9/20	1
COL4A5	ENST00000361603.7	c.1826G>C	p.Gly609Ala	missense_variant	25/51	2		P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked Alport syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Molecular Biology Laboratory, Fundació Puigvert

Feb 01, 2020

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.83
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;D;T
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.0	H;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.4	D;D;.
REVEL	Pathogenic	0.98
Sift	Uncertain	0.017	D;D;.
Sift4G	Uncertain	0.020	D;D;.
Polyphen		1.0	.;D;D
Vest4		0.97
MutPred		0.93		Loss of relative solvent accessibility (P = 0.0676);Loss of relative solvent accessibility (P = 0.0676);.;
MVP		1.0
MPC		0.32
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs104886140; hg19: chrX-107841978;