chr2-227051131-C-T

Variant names:

• chr2-227051131-C-T
• rs13027659
• NM_000092.5:c.2996G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_000092.5(COL4A4):​c.2996G>A​(p.Gly999Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0166 in 1,614,116 control chromosomes in the GnomAD database, including 298 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.013 (18 hom., cov: 32)
  • Exomes 𝑓: 0.017 (280 hom.)
• Consequence: COL4A4 NM_000092.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 5.80
• Publications: 21 publications found

Genes affected

COL4A4 (HGNC:2206): (collagen type IV alpha 4 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. This particular collagen IV subunit, however, is only found in a subset of basement membranes. 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. Mutations in this gene are associated with type II autosomal recessive Alport syndrome (hereditary glomerulonephropathy) and with familial benign hematuria (thin basement membrane disease). Two transcripts, differing only in their transcription start sites, have been identified for this gene and, as is common for collagen genes, multiple polyadenylation sites are found in the 3' UTR. [provided by RefSeq, Jul 2008]

COL4A4 Gene-Disease associations (from GenCC):

• autosomal recessive Alport syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Myriad Women’s Health, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Alport syndrome

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• hematuria, benign familial, 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• autosomal dominant Alport syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_000092.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.029466987).
• BP6: Variant 2-227051131-C-T is Benign according to our data. Variant chr2-227051131-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255027.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0125 (1908/152266) while in subpopulation NFE AF = 0.0213 (1446/68028). AF 95% confidence interval is 0.0203. There are 18 homozygotes in GnomAd4. There are 871 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AR,AD,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000092.5. 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
	COL4A4	NM_000092.5	MANE Select	c.2996G>A	p.Gly999Glu	missense	Exon 33 of 48	NP_000083.3	P53420

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A4	ENST00000396625.5	TSL:5 MANE Select	c.2996G>A	p.Gly999Glu	missense	Exon 33 of 48	ENSP00000379866.3	P53420

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1908 AN: 152148 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.00812

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00981

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0213

Gnomad OTH AF: 0.0149

GnomAD2 exomes AF: 0.0116 AC: 2895 AN: 249534 AF XY: 0.0120

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.00782

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00932

Gnomad NFE exome AF: 0.0191

Gnomad OTH exome AF: 0.0150

GnomAD4 exome AF: 0.0171 AC: 24929 AN: 1461850 Hom.: 280 Cov.: 34 AF XY: 0.0168 AC XY: 12253 AN XY: 727226

African (AFR) AF: 0.00299 AC: 100 AN: 33480

American (AMR) AF: 0.00814 AC: 364 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00233 AC: 61 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00400 AC: 345 AN: 86258

European-Finnish (FIN) AF: 0.00966 AC: 516 AN: 53420

Middle Eastern (MID) AF: 0.0123 AC: 71 AN: 5768

European-Non Finnish (NFE) AF: 0.0204 AC: 22650 AN: 1111968

Other (OTH) AF: 0.0136 AC: 822 AN: 60396

GnomAD4 genome AF: 0.0125 AC: 1908 AN: 152266 Hom.: 18 Cov.: 32 AF XY: 0.0117 AC XY: 871 AN XY: 74442

African (AFR) AF: 0.00315 AC: 131 AN: 41562

American (AMR) AF: 0.00811 AC: 124 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4828

European-Finnish (FIN) AF: 0.00981 AC: 104 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0213 AC: 1446 AN: 68028

Other (OTH) AF: 0.0147 AC: 31 AN: 2108

Alfa AF: 0.0173 Hom.: 87

Bravo AF: 0.0123

TwinsUK AF: 0.0197 AC: 73

ALSPAC AF: 0.0231 AC: 89

ESP6500AA AF: 0.00212 AC: 8

ESP6500EA AF: 0.0157 AC: 129

ExAC AF: 0.0117 AC: 1417

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0213

EpiControl AF: 0.0200

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	1	1	Alport syndrome (2)
-	-	1	Atypical hemolytic-uremic syndrome (1)
-	-	1	COL4A4-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.029	T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		5.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MPC		0.18
ClinPred		0.087	T
GERP RS		5.5
Varity_R		0.94
gMVP		0.95
Mutation Taster		=59/41	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: rs13027659; hg19: chr2-227915847; COSMIC: COSV61631385;