rs104886295

Positions:

• chrX-108692912-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1 PP3 BS2

The NM_033380.3(COL4A5):​c.4693C>G​(p.Pro1565Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000021 in 1,097,832 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000021 (0 hom. 5 hem.)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.91

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 Likely_benign. Variant got -1 ACMG points.

• PM1: In a domain Collagen IV NC1 (size 224) in uniprot entity CO4A5_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_033380.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.823
• BS2: High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.4693C>G	p.Pro1565Ala	missense_variant	50/53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.4693C>G	p.Pro1565Ala	missense_variant	50/53	1	NM_033380.3	ENSP00000331902.7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000109 AC: 2 AN: 183062 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67664

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000210 AC: 23 AN: 1097832 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 5 AN XY: 363258

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: 0.0000261

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 24, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

X-linked Alport syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Dec 21, 2023

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with X-linked Alport syndrome 1 (MIM#301050). Dominant negative is caused mostly by glycine substitutions that affect the conformation of the protein, and loss of function can be caused by either protein truncating or missense variants (PMID: 24046192, 12028435). (I) 0110 - This gene is associated with X-linked dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity There is intrafamilial variability among affected carrier females, possibly due to variable X-inactivation (PMID: 14514738). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to alanine. (I) 0253 - This variant is hemizygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes, 0 hemizygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated C-terminal tandem repeated domain in type 4 procollagen (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been submitted to ClinVar twice as a VUS, with one individual being affected with Alport syndrome (GeneDx personal communication). This variant was also identified in an individual with Alport syndrome in the literature; however, it did not segregate with disease in the family (PMID: 10094548). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	.;D;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.8	.;M;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.024	D;D;D
Polyphen		0.99	.;D;.
Vest4		0.65
MutPred		0.33		.;Loss of disorder (P = 0.0833);.;
MVP		0.81
MPC		1.0
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.72
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs104886295; hg19: chrX-107936142;