chrX-108603045-G-C

Variant names:

• chrX-108603045-G-C
• rs104886166
• NM_033380.3:c.2228G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 9P and 4B. PM1 PM5 PP2 PP3_Strong BS2

The NM_033380.3(COL4A5):​c.2228G>C​(p.Gly743Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,061,204 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G743V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000012 (0 hom. 5 hem.)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.17
• Publications: 4 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_033380.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-108603045-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3382913.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.967
• BS2: High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.2228G>C	p.Gly743Ala	missense_variant	Exon 28 of 53	ENST00000328300.11	NP_203699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.2228G>C	p.Gly743Ala	missense_variant	Exon 28 of 53	1	NM_033380.3	ENSP00000331902.7
COL4A5	ENST00000483338.1	c.1052G>C	p.Gly351Ala	missense_variant	Exon 12 of 20	1		ENSP00000495685.1
COL4A5	ENST00000361603.7	c.2228G>C	p.Gly743Ala	missense_variant	Exon 28 of 51	2		ENSP00000354505.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.0000123 AC: 13 AN: 1061204 Hom.: 0 Cov.: 26 AF XY: 0.0000149 AC XY: 5 AN XY: 334770

African (AFR) AF: 0.00 AC: 0 AN: 25742

American (AMR) AF: 0.00 AC: 0 AN: 33495

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18851

East Asian (EAS) AF: 0.00 AC: 0 AN: 29534

South Asian (SAS) AF: 0.0000195 AC: 1 AN: 51332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39197

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3872

European-Non Finnish (NFE) AF: 0.0000147 AC: 12 AN: 814496

Other (OTH) AF: 0.00 AC: 0 AN: 44685

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.82
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0	.;D;D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.1	H;H;.
PhyloP100		9.2
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.5	D;D;.
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.032	D;D;.
Vest4		0.89
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.98
Mutation Taster		=1/99	disease causing

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: rs104886166; hg19: chrX-107846275;