rs104886447

Variant names:

• chrX-108580706-G-A
• rs104886447
• NM_033380.3:c.859G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-108580706-G-A
• chrX-108580706-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_033380.3(COL4A5):​c.859G>A​(p.Glu287Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,506 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E287E) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.28
• Publications: 0 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_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_033380.3
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.829

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.859G>A	p.Glu287Lys	missense	Exon 15 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.859G>A	p.Glu287Lys	missense	Exon 15 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.859G>A	p.Glu287Lys	missense	Exon 15 of 53	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000949143.1		c.859G>A	p.Glu287Lys	missense	Exon 15 of 51	ENSP00000619202.1
	COL4A5	ENST00000361603.7	TSL:2	c.859G>A	p.Glu287Lys	missense	Exon 15 of 51	ENSP00000354505.2	P29400-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097506 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 362910

African (AFR) AF: 0.00 AC: 0 AN: 26383

American (AMR) AF: 0.00 AC: 0 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.00 AC: 0 AN: 54132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841485

Other (OTH) AF: 0.00 AC: 0 AN: 46058

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Benign	0.98	L
PhyloP100		6.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.72
Sift	Benign	0.12	T
Sift4G	Uncertain	0.041	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.50		Gain of methylation at E287 (P = 0.0085)
MVP		0.89
MPC		0.34
ClinPred		0.88	D
GERP RS		5.5
Varity_R		0.59
gMVP		0.54
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs104886447; hg19: chrX-107823936; COSMIC: COSV108114025; COSMIC: COSV108114025;