X-108591223-T-G

Variant names:

• chrX-108591223-T-G
• rs2272946
• NM_033380.3:c.1331T>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_033380.3(COL4A5):​c.1331T>G​(p.Ile444Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0242 in 1,206,143 control chromosomes in the GnomAD database, including 2,714 homozygotes. There are 8,304 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I444V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.10 (1300 hom., 3262 hem., cov: 23)
  • Exomes 𝑓: 0.016 (1414 hom. 5042 hem.)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.10
• Publications: 16 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: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 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=0.0024892688).
• BP6: Variant X-108591223-T-G is Benign according to our data. Variant chrX-108591223-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 24398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

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.1331T>G	p.Ile444Ser	missense	Exon 20 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.1331T>G	p.Ile444Ser	missense	Exon 20 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.1331T>G	p.Ile444Ser	missense	Exon 20 of 53	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000483338.1	TSL:1	c.155T>G	p.Ile52Ser	missense	Exon 4 of 20	ENSP00000495685.1	Q49AM6
	COL4A5	ENST00000949143.1		c.1331T>G	p.Ile444Ser	missense	Exon 20 of 51	ENSP00000619202.1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 11646 AN: 111986 Hom.: 1300 Cov.: 23

Gnomad AFR AF: 0.336

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0554

Gnomad ASJ AF: 0.00301

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.0206

Gnomad FIN AF: 0.000163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00130

Gnomad OTH AF: 0.0894

GnomAD2 exomes AF: 0.0447 AC: 8115 AN: 181571 AF XY: 0.0334

Gnomad AFR exome AF: 0.340

Gnomad AMR exome AF: 0.0431

Gnomad ASJ exome AF: 0.00351

Gnomad EAS exome AF: 0.149

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000851

Gnomad OTH exome AF: 0.0240

GnomAD4 exome AF: 0.0160 AC: 17507 AN: 1094106 Hom.: 1414 Cov.: 30 AF XY: 0.0140 AC XY: 5042 AN XY: 360496

African (AFR) AF: 0.340 AC: 8913 AN: 26186

American (AMR) AF: 0.0466 AC: 1633 AN: 35041

Ashkenazi Jewish (ASJ) AF: 0.00362 AC: 70 AN: 19343

East Asian (EAS) AF: 0.123 AC: 3723 AN: 30178

South Asian (SAS) AF: 0.0151 AC: 813 AN: 53963

European-Finnish (FIN) AF: 0.000173 AC: 7 AN: 40510

Middle Eastern (MID) AF: 0.00992 AC: 30 AN: 3023

European-Non Finnish (NFE) AF: 0.000602 AC: 506 AN: 839995

Other (OTH) AF: 0.0395 AC: 1812 AN: 45867

GnomAD4 genome AF: 0.104 AC: 11658 AN: 112037 Hom.: 1300 Cov.: 23 AF XY: 0.0952 AC XY: 3262 AN XY: 34247

African (AFR) AF: 0.336 AC: 10301 AN: 30682

American (AMR) AF: 0.0552 AC: 590 AN: 10692

Ashkenazi Jewish (ASJ) AF: 0.00301 AC: 8 AN: 2656

East Asian (EAS) AF: 0.143 AC: 500 AN: 3507

South Asian (SAS) AF: 0.0203 AC: 55 AN: 2714

European-Finnish (FIN) AF: 0.000163 AC: 1 AN: 6151

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00130 AC: 69 AN: 53213

Other (OTH) AF: 0.0883 AC: 134 AN: 1518

Alfa AF: 0.0536 Hom.: 2927

Bravo AF: 0.120

ESP6500AA AF: 0.332 AC: 1273

ESP6500EA AF: 0.00164 AC: 11

ExAC AF: 0.0468 AC: 5678

EpiCase AF: 0.000819

EpiControl AF: 0.000831

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	3	X-linked Alport syndrome (3)
-	-	1	Focal segmental glomerulosclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	7.2
DANN	Benign	0.65
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.23
Sift	Benign	0.56	T
Sift4G	Benign	0.40	T
Polyphen		0.017	B
Vest4		0.11
MPC		0.44
ClinPred		0.0032	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.16
gMVP		0.78
Mutation Taster		=97/3	polymorphism (auto)

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: rs2272946; hg19: chrX-107834453; COSMIC: COSV60358466;