X-108686060-C-A

Variant names:

• chrX-108686060-C-A
• rs104886270
• NM_033380.3:c.4246C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_033380.3(COL4A5):​c.4246C>A​(p.Arg1416Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,340 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1416C) has been classified as Uncertain significance.

• 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: 0.472
• 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: Uncertain_significance. The variant received 3 ACMG points.

• 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.

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.4246C>A	p.Arg1416Ser	missense	Exon 48 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.4228C>A	p.Arg1410Ser	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.4246C>A	p.Arg1416Ser	missense	Exon 48 of 53	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000949143.1		c.4240C>A	p.Arg1414Ser	missense	Exon 46 of 51	ENSP00000619202.1
	COL4A5	ENST00000361603.7	TSL:2	c.4228C>A	p.Arg1410Ser	missense	Exon 46 of 51	ENSP00000354505.2	P29400-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097340 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 362784

African (AFR) AF: 0.00 AC: 0 AN: 26379

American (AMR) AF: 0.00 AC: 0 AN: 35169

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19374

East Asian (EAS) AF: 0.00 AC: 0 AN: 30176

South Asian (SAS) AF: 0.00 AC: 0 AN: 54078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40493

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4071

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841544

Other (OTH) AF: 0.0000217 AC: 1 AN: 46056

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	1.3	L
PhyloP100		0.47
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.63	N
REVEL	Uncertain	0.34
Sift	Benign	0.41	T
Sift4G	Benign	0.69	T
Polyphen		0.98	D
Vest4		0.37
MutPred		0.42		Gain of glycosylation at R1410 (P = 0.0105)
MVP		0.89
MPC		1.0
ClinPred		0.76	D
GERP RS		5.1
Varity_R		0.26
gMVP		0.41
Mutation Taster		=75/25	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: rs104886270; hg19: chrX-107929290;