rs104886399

Variant names:

• chrX-108677614-A-G
• rs104886399
• NM_033380.3:c.3923A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1 PP2 BP4 BP6 BS2

The NM_033380.3(COL4A5):​c.3923A>G​(p.Gln1308Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,209,134 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q1308Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., 3 hem., cov: 24)
  • Exomes 𝑓: 0.000022 (0 hom. 10 hem.)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.19
• Publications: 3 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 -3 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 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). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked Alport syndrome, Alport syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3822859).
• BP6: Variant X-108677614-A-G is Benign according to our data. Variant chrX-108677614-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 783151.
• BS2: High Hemizygotes in GnomAd4 at 3 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.3923A>G	p.Gln1308Arg	missense	Exon 44 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.3905A>G	p.Gln1302Arg	missense	Exon 42 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.3923A>G	p.Gln1308Arg	missense	Exon 44 of 53	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000949143.1		c.3917A>G	p.Gln1306Arg	missense	Exon 42 of 51	ENSP00000619202.1
	COL4A5	ENST00000361603.7	TSL:2	c.3905A>G	p.Gln1302Arg	missense	Exon 42 of 51	ENSP00000354505.2	P29400-1

Frequencies

GnomAD3 genomes AF: 0.0000535 AC: 6 AN: 112080 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000948

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000562

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000564

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000383 AC: 7 AN: 182905 AF XY: 0.0000593

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000732

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000613

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 24 AN: 1097054 Hom.: 0 Cov.: 30 AF XY: 0.0000276 AC XY: 10 AN XY: 362700

African (AFR) AF: 0.00 AC: 0 AN: 26362

American (AMR) AF: 0.0000854 AC: 3 AN: 35136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19346

East Asian (EAS) AF: 0.00 AC: 0 AN: 30155

South Asian (SAS) AF: 0.00 AC: 0 AN: 54105

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40478

Middle Eastern (MID) AF: 0.000244 AC: 1 AN: 4103

European-Non Finnish (NFE) AF: 0.0000202 AC: 17 AN: 841340

Other (OTH) AF: 0.0000652 AC: 3 AN: 46029

GnomAD4 genome AF: 0.0000535 AC: 6 AN: 112080 Hom.: 0 Cov.: 24 AF XY: 0.0000876 AC XY: 3 AN XY: 34238

African (AFR) AF: 0.00 AC: 0 AN: 30882

American (AMR) AF: 0.0000948 AC: 1 AN: 10543

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.000562 AC: 2 AN: 3561

South Asian (SAS) AF: 0.00 AC: 0 AN: 2683

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000564 AC: 3 AN: 53161

Other (OTH) AF: 0.00 AC: 0 AN: 1504

Alfa AF: 0.0000341 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.0000546

EpiControl AF: 0.000238

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	-	1	X-linked Alport syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	19
DANN	Benign	0.86
DEOGEN2	Uncertain	0.46	T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	0.33	N
PhyloP100		1.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.78	N
REVEL	Uncertain	0.48
Sift	Benign	0.48	T
Sift4G	Benign	0.55	T
Polyphen		0.64	P
Vest4		0.31
MutPred		0.37		Gain of methylation at Q1302 (P = 0.0168)
MVP		1.0
MPC		0.32
ClinPred		0.15	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.29
Mutation Taster		=98/2	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: rs104886399; hg19: chrX-107920844;