X-108686096-C-T

Variant names:

• chrX-108686096-C-T
• rs144282156
• NM_033380.3:c.4282C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 7P and 9B. PM1 PM5 PP2 PP3_Moderate BP6 BS1 BS2

The NM_033380.3(COL4A5):​c.4282C>T​(p.Arg1428Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00085 in 1,208,447 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 340 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. R1428H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., 11 hem., cov: 23)
  • Exomes 𝑓: 0.00090 (0 hom. 329 hem.)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 1.32
• Publications: 9 publications found

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]

COL4A5 Gene-Disease associations (from GenCC):

• Alport syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: G2P, ClinGen
• X-linked Alport syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Myriad Women’s Health

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_033380.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-108686097-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1030828.
• 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). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked Alport syndrome, Alport syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902
• BP6: Variant X-108686096-C-T is Benign according to our data. Variant chrX-108686096-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 242725.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000351 (39/111138) while in subpopulation NFE AF = 0.000604 (32/52998). AF 95% confidence interval is 0.000439. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 11 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033380.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	NM_033380.3	MANE Select	c.4282C>T	p.Arg1428Cys	missense	Exon 48 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.4264C>T	p.Arg1422Cys	missense	Exon 46 of 51	NP_000486.1	P29400-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	ENST00000328300.11	TSL:1 MANE Select	c.4282C>T	p.Arg1428Cys	missense	Exon 48 of 53	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000949143.1		c.4276C>T	p.Arg1426Cys	missense	Exon 46 of 51	ENSP00000619202.1
	COL4A5	ENST00000361603.7	TSL:2	c.4264C>T	p.Arg1422Cys	missense	Exon 46 of 51	ENSP00000354505.2	P29400-1

Frequencies

GnomAD3 genomes AF: 0.000351 AC: 39 AN: 111085 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000283

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000168

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000604

Gnomad OTH AF: 0.000670

GnomAD2 exomes AF: 0.000345 AC: 63 AN: 182384 AF XY: 0.000388

Gnomad AFR exome AF: 0.000153

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000188

Gnomad NFE exome AF: 0.000701

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000900 AC: 988 AN: 1097309 Hom.: 0 Cov.: 30 AF XY: 0.000907 AC XY: 329 AN XY: 362753

African (AFR) AF: 0.000152 AC: 4 AN: 26373

American (AMR) AF: 0.0000284 AC: 1 AN: 35164

Ashkenazi Jewish (ASJ) AF: 0.000103 AC: 2 AN: 19373

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30176

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54066

European-Finnish (FIN) AF: 0.000370 AC: 15 AN: 40490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4072

European-Non Finnish (NFE) AF: 0.00111 AC: 932 AN: 841541

Other (OTH) AF: 0.000695 AC: 32 AN: 46054

GnomAD4 genome AF: 0.000351 AC: 39 AN: 111138 Hom.: 0 Cov.: 23 AF XY: 0.000330 AC XY: 11 AN XY: 33344

African (AFR) AF: 0.000131 AC: 4 AN: 30570

American (AMR) AF: 0.00 AC: 0 AN: 10454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2634

East Asian (EAS) AF: 0.000284 AC: 1 AN: 3516

South Asian (SAS) AF: 0.00 AC: 0 AN: 2614

European-Finnish (FIN) AF: 0.000168 AC: 1 AN: 5945

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.000604 AC: 32 AN: 52998

Other (OTH) AF: 0.000662 AC: 1 AN: 1511

Alfa AF: 0.000473 Hom.: 14

Bravo AF: 0.000431

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000743 AC: 5

ExAC AF: 0.000329 AC: 40

EpiCase AF: 0.000491

EpiControl AF: 0.000595

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	3	X-linked Alport syndrome (3)
-	1	-	COL4A5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.3
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.015	D
Sift4G	Benign	0.065	T
Polyphen		0.40	B
Vest4		0.91
MVP		0.97
MPC		1.2
ClinPred		0.11	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.37
gMVP		0.53
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs144282156; hg19: chrX-107929326; COSMIC: COSV60368898;