rs104886285

Variant names:

• chrX-108692769-G-A
• rs104886285
• NM_033380.3:c.4550G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1 PP2 BS2_Supporting

The NM_033380.3(COL4A5):​c.4550G>A​(p.Arg1517His) variant causes a missense change. The variant allele was found at a frequency of 0.0000165 in 1,209,389 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1517C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.000016 (0 hom. 3 hem.)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.84

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_033380.3
• 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). GenCC associations: The gene is linked to X-linked Alport syndrome, Alport syndrome.
• BS2: High Hemizygotes in GnomAd4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.4550G>A	p.Arg1517His	missense_variant	Exon 50 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.4550G>A	p.Arg1517His	missense_variant	Exon 50 of 53	1	NM_033380.3	ENSP00000331902.7

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111497 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000281

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000166

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000164 AC: 3 AN: 182911 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 18 AN: 1097892 Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 3 AN XY: 363304

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 26392

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 35187

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 19376

Gnomad4 EAS exome AF: 0.000132 AC: 4 AN: 30202

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 54140

Gnomad4 FIN exome AF: 0.0000247 AC: 1 AN: 40524

Gnomad4 NFE exome AF: 0.0000154 AC: 13 AN: 841849

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 46088

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111497 Hom.: 0 Cov.: 22 AF XY: 0.0000594 AC XY: 2 AN XY: 33665

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000281 AC: 0.000281373 AN: 0.000281373

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.000166 AC: 0.000166279 AN: 0.000166279

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000238 Hom.: 1

Bravo AF: 0.0000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Apr 25, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL4A5 c.4532G>A (p.Arg1511His) results in a non-conservative amino acid change located in the Collagen IV, non-collagenous domain (IPR001442) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 (i.e., 3 heterozygous carriers, including 2 females and 1 male) in 182911 control chromosomes (gnomAD v2, Exomes cohort). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4532G>A has been reported in the literature in individuals affected with Alport Syndrome (e.g., Plant_1999, Cheong_2000, Azaiez_2018, Zhao_2019, Park_2020), however, the variant was also reported in an asymptomatic male (Zhao_2019). Therefore these data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant disrupts type IV collagen heterotrimer formation but was still found to be secreted by cells (e.g., Kobayashi_2008). The following publications have been ascertained in the context of this evaluation (PMID: 30245029, 10684360, 18083113, 32604935, 10094548, 30968591). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Benign:1

Feb 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	.;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.4	.;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.3	N;N
REVEL	Pathogenic	0.79
Sift	Benign	0.041	D;D
Sift4G	Benign	0.11	T;T
Polyphen		0.73	.;P
Vest4		0.33
MVP		0.99
MPC		0.63
ClinPred		0.39	T
GERP RS		4.8
Varity_R		0.72
gMVP		0.90
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs104886285; hg19: chrX-107935999; COSMIC: COSV60355867; COSMIC: COSV60355867;