rs104886270

chrX-108686060-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_033380.3(COL4A5):c.4246C>T(p.Arg1416Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000513 in 1,208,887 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 24 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 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. R1416H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000081 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000048 (0 hom. 22 hem.)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 0.472

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 -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.851
• BS2: High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.4246C>T	p.Arg1416Cys	missense_variant	48/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.4246C>T	p.Arg1416Cys	missense_variant	48/53	1	NM_033380.3

Frequencies

GnomAD3 genomes AF: 0.0000807 AC: 9 AN: 111494 Hom.: 0 Cov.: 23 AF XY: 0.0000594 AC XY: 2 AN XY: 33680

Gnomad AFR AF: 0.0000653

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000951

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000942

Gnomad OTH AF: 0.000671

GnomAD3 exomes AF: 0.0000383 AC: 7 AN: 182632 Hom.: 0 AF XY: 0.0000744 AC XY: 5 AN XY: 67228

Gnomad AFR exome AF: 0.0000762

Gnomad AMR exome AF: 0.0000731

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: 0.0000491

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000483 AC: 53 AN: 1097339 Hom.: 0 Cov.: 30 AF XY: 0.0000606 AC XY: 22 AN XY: 362783

Gnomad4 AFR exome AF: 0.000114

Gnomad4 AMR exome AF: 0.0000569

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000547

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.0000807 AC: 9 AN: 111548 Hom.: 0 Cov.: 23 AF XY: 0.0000593 AC XY: 2 AN XY: 33744

Gnomad4 AFR AF: 0.0000652

Gnomad4 AMR AF: 0.0000950

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000942

Gnomad4 OTH AF: 0.000663

Bravo AF: 0.0000567

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

X-linked Alport syndrome Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Sep 28, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 28, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 17, 2021	- -

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the X position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the X position is not a common mechanism of disease; This variant is associated with the following publications: (PMID: 8651296, 9452056) -
Uncertain significance, criteria provided, single submitter	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Oct 25, 2023	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 10, 2023	Variant summary: COL4A5 c.4228C>T (p.Arg1410Cys) results in a non-conservative amino acid change located in the triple-helical region 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 3.8e-05 in 182632 control chromosomes in the gnomAD database, including 5 hemizygotes, providing evidence supporting a benign role. c.4228C>T has been reported in the literature in at least one male individual and as a heterozygous genotype in one female individual affected with Alport Syndrome 1, X-Linked Recessive, and in both cases, the variant was reported to segregate with the disease phenotype, however no additional information (i.e. pedigrees, number and/or genotype of affected or unaffected family members) was provided. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9452056, 35580552, 8651296). Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as either VUS (n=6) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Uncertain	25
Dann	Pathogenic	1.0
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Pathogenic	0.90	D
MutationTaster	Benign	1.0	A;A
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.65
Sift	Benign	0.11	T;D
Sift4G	Benign	0.067	T;D
Polyphen		1.0	.;D
Vest4		0.89
MVP		0.98
MPC		1.2
ClinPred		0.58	D
GERP RS		5.1
Varity_R		0.37
gMVP		0.47

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: rs104886270; hg19: chrX-107929290; COSMIC: COSV60377043;