rs80243096

Variant names:

• chr2-227052374-T-C
• rs80243096
• NM_000092.5:c.2899A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000092.5(COL4A4):​c.2899A>G​(p.Ile967Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00797 in 1,612,552 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (30 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (77 hom.)
• Consequence: COL4A4 NM_000092.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.247
• Publications: 8 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 -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000092.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0029687583).
• BP6: Variant 2-227052374-T-C is Benign according to our data. Variant chr2-227052374-T-C is described in ClinVar as Benign. ClinVar VariationId is 255025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0164 (2490/152288) while in subpopulation AFR AF = 0.0426 (1769/41556). AF 95% confidence interval is 0.0409. There are 30 homozygotes in GnomAd4. There are 1159 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 SD,AR,AD 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.2899A>G	p.Ile967Val	missense	Exon 32 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.2899A>G	p.Ile967Val	missense	Exon 32 of 48	ENSP00000379866.3	P53420

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2487 AN: 152170 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0426

Gnomad AMI AF: 0.0538

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00657

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.00712 AC: 1777 AN: 249560 AF XY: 0.00626

Gnomad AFR exome AF: 0.0458

Gnomad AMR exome AF: 0.00652

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00642

Gnomad OTH exome AF: 0.00709

GnomAD4 exome AF: 0.00709 AC: 10356 AN: 1460264 Hom.: 77 Cov.: 30 AF XY: 0.00678 AC XY: 4925 AN XY: 726604

African (AFR) AF: 0.0496 AC: 1658 AN: 33432

American (AMR) AF: 0.00698 AC: 312 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00379 AC: 99 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.000905 AC: 78 AN: 86224

European-Finnish (FIN) AF: 0.000374 AC: 20 AN: 53414

Middle Eastern (MID) AF: 0.00746 AC: 43 AN: 5764

European-Non Finnish (NFE) AF: 0.00690 AC: 7668 AN: 1110550

Other (OTH) AF: 0.00792 AC: 478 AN: 60352

GnomAD4 genome AF: 0.0164 AC: 2490 AN: 152288 Hom.: 30 Cov.: 32 AF XY: 0.0156 AC XY: 1159 AN XY: 74460

African (AFR) AF: 0.0426 AC: 1769 AN: 41556

American (AMR) AF: 0.0112 AC: 171 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00657 AC: 447 AN: 68014

Other (OTH) AF: 0.0185 AC: 39 AN: 2112

Alfa AF: 0.00995 Hom.: 37

Bravo AF: 0.0187

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.0393 AC: 145

ESP6500EA AF: 0.00648 AC: 53

ExAC AF: 0.00730 AC: 882

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00862

EpiControl AF: 0.00771

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Alport syndrome (2)
-	-	1	Autosomal recessive Alport syndrome (1)
-	-	1	Focal segmental glomerulosclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	3.9
DANN	Benign	0.85
DEOGEN2	Benign	0.078	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.25
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.12
Sift	Benign	0.96	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.17
MVP		0.58
MPC		0.12
ClinPred		0.0014	T
GERP RS		-0.43
Varity_R		0.023
gMVP		0.092
Mutation Taster		=100/0	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: rs80243096; hg19: chr2-227917090;