X-108440135-C-A

Variant names:

• chrX-108440135-C-A
• NM_033380.3:c.10C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_033380.3(COL4A5):​c.10C>A​(p.Arg4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 20)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.31
• 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 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.28576177).

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.10C>A	p.Arg4Ser	missense	Exon 1 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.10C>A	p.Arg4Ser	missense	Exon 1 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.10C>A	p.Arg4Ser	missense	Exon 1 of 53	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000477429.1	TSL:1	n.292C>A		non_coding_transcript_exon	Exon 1 of 2
	COL4A5	ENST00000949143.1		c.10C>A	p.Arg4Ser	missense	Exon 1 of 51	ENSP00000619202.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 20

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.096	T
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.48	N
REVEL	Uncertain	0.37
Sift	Benign	0.12	T
Sift4G	Uncertain	0.036	D
Polyphen		0.039	B
Vest4		0.35
MutPred		0.41		Loss of MoRF binding (P = 0.0018)
MVP		0.71
MPC		0.34
ClinPred		0.60	D
GERP RS		4.7
PromoterAI		-0.0026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.38
gMVP		0.67
Mutation Taster		=73/27	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

hg19: chrX-107683365;