X-108622766-G-T

Variant names:

• chrX-108622766-G-T
• rs78972735
• NM_033380.3:c.2858G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_033380.3(COL4A5):​c.2858G>T​(p.Gly953Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,209,432 control chromosomes in the GnomAD database, including 8 homozygotes. There are 474 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). Synonymous variant affecting the same amino acid position (i.e. G953G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., 71 hem., cov: 23)
  • Exomes 𝑓: 0.0010 (8 hom. 403 hem.)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 7.25
• Publications: 30 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 -12 ACMG points.

• 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=0.008373588).
• BP6: Variant X-108622766-G-T is Benign according to our data. Variant chrX-108622766-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 24573.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00158 (178/112480) while in subpopulation EAS AF = 0.0374 (132/3529). AF 95% confidence interval is 0.0322. There are 0 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 71 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	NM_033380.3	MANE Select	c.2858G>T	p.Gly953Val	missense	Exon 33 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.2858G>T	p.Gly953Val	missense	Exon 33 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.2858G>T	p.Gly953Val	missense	Exon 33 of 53	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000483338.1	TSL:1	c.1682G>T	p.Gly561Val	missense	Exon 17 of 20	ENSP00000495685.1	Q49AM6
	COL4A5	ENST00000949143.1		c.2870G>T	p.Gly957Val	missense	Exon 33 of 51	ENSP00000619202.1

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 179 AN: 112429 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000646

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000374

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0376

Gnomad SAS AF: 0.00661

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000375

Gnomad OTH AF: 0.00132

GnomAD2 exomes AF: 0.00360 AC: 659 AN: 182930 AF XY: 0.00337

Gnomad AFR exome AF: 0.000533

Gnomad AMR exome AF: 0.000183

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0368

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00104 AC: 1146 AN: 1096952 Hom.: 8 Cov.: 30 AF XY: 0.00111 AC XY: 403 AN XY: 362498

African (AFR) AF: 0.000227 AC: 6 AN: 26383

American (AMR) AF: 0.000114 AC: 4 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19376

East Asian (EAS) AF: 0.0223 AC: 673 AN: 30189

South Asian (SAS) AF: 0.00529 AC: 286 AN: 54102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3811

European-Non Finnish (NFE) AF: 0.0000202 AC: 17 AN: 841334

Other (OTH) AF: 0.00348 AC: 160 AN: 46027

GnomAD4 genome AF: 0.00158 AC: 178 AN: 112480 Hom.: 0 Cov.: 23 AF XY: 0.00205 AC XY: 71 AN XY: 34670

African (AFR) AF: 0.000645 AC: 20 AN: 31030

American (AMR) AF: 0.000374 AC: 4 AN: 10699

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.0374 AC: 132 AN: 3529

South Asian (SAS) AF: 0.00663 AC: 18 AN: 2716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.0000375 AC: 2 AN: 53265

Other (OTH) AF: 0.00130 AC: 2 AN: 1533

Alfa AF: 0.00102 Hom.: 7

Bravo AF: 0.00146

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00342 AC: 415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	X-linked Alport syndrome (4)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	COL4A5-related disorder (1)
-	-	1	Kidney disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.78
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0084	T
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.34
MVP		0.99
MPC		0.37
ClinPred		0.11	T
GERP RS		6.0
PromoterAI		-0.016	Neutral
Varity_R		0.99
gMVP		1.0
Mutation Taster		=84/16	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: rs78972735; hg19: chrX-107865996;