rs104886192

Variant names:

• chrX-108621817-A-G
• rs104886192
• NM_033380.3:c.2692A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM1 PP2 BP4_Strong BS1_Supporting BS2

The NM_033380.3(COL4A5):​c.2692A>G​(p.Met898Val) variant causes a missense change. The variant allele was found at a frequency of 0.000221 in 1,203,910 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 85 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M898I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.00022 (0 hom. 77 hem.)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 B:7
• Conservation: PhyloP100: 5.54
• Publications: 5 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: ClinGen, G2P
• X-linked Alport syndrome

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

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 1 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=0.053881973).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000196 (22/112245) while in subpopulation SAS AF = 0.00147 (4/2714). AF 95% confidence interval is 0.000503. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd4 at 8 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	NM_033380.3	MANE Select	c.2692A>G	p.Met898Val	missense	Exon 32 of 53	NP_203699.1
	COL4A5	NM_000495.5		c.2692A>G	p.Met898Val	missense	Exon 32 of 51	NP_000486.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	ENST00000328300.11	TSL:1 MANE Select	c.2692A>G	p.Met898Val	missense	Exon 32 of 53	ENSP00000331902.7
	COL4A5	ENST00000483338.1	TSL:1	c.1516A>G	p.Met506Val	missense	Exon 16 of 20	ENSP00000495685.1
	COL4A5	ENST00000361603.7	TSL:2	c.2692A>G	p.Met898Val	missense	Exon 32 of 51	ENSP00000354505.2

Frequencies

GnomAD3 genomes AF: 0.000196 AC: 22 AN: 112245 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00339

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00147

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000150

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000304 AC: 55 AN: 181177 AF XY: 0.000425

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00324

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.000224 AC: 244 AN: 1091665 Hom.: 0 Cov.: 28 AF XY: 0.000215 AC XY: 77 AN XY: 357385

African (AFR) AF: 0.00 AC: 0 AN: 26311

American (AMR) AF: 0.00 AC: 0 AN: 35170

Ashkenazi Jewish (ASJ) AF: 0.00326 AC: 63 AN: 19333

East Asian (EAS) AF: 0.00 AC: 0 AN: 30151

South Asian (SAS) AF: 0.000856 AC: 46 AN: 53724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40486

Middle Eastern (MID) AF: 0.000243 AC: 1 AN: 4119

European-Non Finnish (NFE) AF: 0.000137 AC: 115 AN: 836514

Other (OTH) AF: 0.000414 AC: 19 AN: 45857

GnomAD4 genome AF: 0.000196 AC: 22 AN: 112245 Hom.: 0 Cov.: 23 AF XY: 0.000233 AC XY: 8 AN XY: 34395

African (AFR) AF: 0.0000324 AC: 1 AN: 30864

American (AMR) AF: 0.00 AC: 0 AN: 10587

Ashkenazi Jewish (ASJ) AF: 0.00339 AC: 9 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3569

South Asian (SAS) AF: 0.00147 AC: 4 AN: 2714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6195

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.000150 AC: 8 AN: 53231

Other (OTH) AF: 0.00 AC: 0 AN: 1503

Alfa AF: 0.000444 Hom.: 6

Bravo AF: 0.000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000297 AC: 36

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	2	X-linked Alport syndrome (5)
-	-	3	not provided (3)
1	-	-	Autosomal dominant Alport syndrome (1)
-	-	1	COL4A5-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Uncertain	0.49	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.45	N
PhyloP100		5.5
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.47
Sift	Benign	0.21	T
Sift4G	Benign	0.60	T
Polyphen		0.0050	B
Vest4		0.17
MVP		0.99
MPC		0.30
ClinPred		0.051	T
GERP RS		4.5
Varity_R		0.26
gMVP		0.86
Mutation Taster		=62/38	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		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: rs104886192; hg19: chrX-107865047;