2-227008067-G-C

Variant names:

• chr2-227008067-G-C
• rs190148408
• NM_000092.5:c.4760C>G

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.4760C>G​(p.Pro1587Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00342 in 1,613,882 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1587L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (16 hom.)
• Consequence: COL4A4 NM_000092.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:8
• Conservation: PhyloP100: 0.778
• Publications: 12 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 0 benign, 11 uncertain in NM_000092.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.030847788).
• BP6: Variant 2-227008067-G-C is Benign according to our data. Variant chr2-227008067-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 447189.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00213 (324/152350) while in subpopulation NFE AF = 0.00367 (250/68032). AF 95% confidence interval is 0.0033. There are 1 homozygotes in GnomAd4. There are 142 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 16 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.4760C>G	p.Pro1587Arg	missense	Exon 47 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.4760C>G	p.Pro1587Arg	missense	Exon 47 of 48	ENSP00000379866.3	P53420
	COL4A4	ENST00000682098.1		c.362C>G	p.Pro121Arg	missense	Exon 2 of 3	ENSP00000508331.1	A0A804HLF6

Frequencies

GnomAD3 genomes AF: 0.00213 AC: 324 AN: 152232 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00367

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00203 AC: 504 AN: 248148 AF XY: 0.00207

Gnomad AFR exome AF: 0.000392

Gnomad AMR exome AF: 0.000522

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000470

Gnomad NFE exome AF: 0.00338

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.00356 AC: 5201 AN: 1461532 Hom.: 16 Cov.: 32 AF XY: 0.00340 AC XY: 2473 AN XY: 727072

African (AFR) AF: 0.000717 AC: 24 AN: 33480

American (AMR) AF: 0.000537 AC: 24 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00199 AC: 52 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.00150 AC: 129 AN: 86250

European-Finnish (FIN) AF: 0.000433 AC: 23 AN: 53112

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00427 AC: 4750 AN: 1111968

Other (OTH) AF: 0.00315 AC: 190 AN: 60396

GnomAD4 genome AF: 0.00213 AC: 324 AN: 152350 Hom.: 1 Cov.: 33 AF XY: 0.00191 AC XY: 142 AN XY: 74504

African (AFR) AF: 0.000673 AC: 28 AN: 41580

American (AMR) AF: 0.00131 AC: 20 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4826

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00367 AC: 250 AN: 68032

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00278 Hom.: 0

Bravo AF: 0.00221

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000771 AC: 3

ESP6500EA AF: 0.00326 AC: 27

ExAC AF: 0.00179 AC: 217

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00332

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)
-	2	1	Alport syndrome (3)
-	-	3	not specified (3)
-	-	1	COL4A4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	17
DANN	Benign	0.22
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.031	T
MetaSVM	Uncertain	-0.054	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.78
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.33
Sift	Benign	0.90	T
Sift4G	Benign	0.79	T
Polyphen		0.91	P
Vest4		0.43
MVP		0.77
MPC		0.15
ClinPred		0.049	T
GERP RS		5.0
Varity_R		0.33
gMVP		0.30
Mutation Taster		=64/36	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: rs190148408; hg19: chr2-227872783; COSMIC: COSV61635993;