chr2-227080465-T-C

Variant names:

• chr2-227080465-T-C
• rs35998949
• NM_000092.5:c.1781A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000092.5(COL4A4):​c.1781A>G​(p.Glu594Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00392 in 1,614,088 control chromosomes in the GnomAD database, including 231 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E594E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.021 (112 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (119 hom.)
• Consequence: COL4A4 NM_000092.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.42
• Publications: 6 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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 12 uncertain in NM_000092.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0029699206).
• BP6: Variant 2-227080465-T-C is Benign according to our data. Variant chr2-227080465-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 218426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0698 is higher than 0.05.

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.1781A>G	p.Glu594Gly	missense	Exon 24 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.1781A>G	p.Glu594Gly	missense	Exon 24 of 48	ENSP00000379866.3	P53420

Frequencies

GnomAD3 genomes AF: 0.0209 AC: 3181 AN: 152102 Hom.: 112 Cov.: 32

Gnomad AFR AF: 0.0719

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0168

GnomAD2 exomes AF: 0.00521 AC: 1301 AN: 249558 AF XY: 0.00402

Gnomad AFR exome AF: 0.0732

Gnomad AMR exome AF: 0.00342

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000300

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00215 AC: 3137 AN: 1461868 Hom.: 119 Cov.: 31 AF XY: 0.00187 AC XY: 1361 AN XY: 727230

African (AFR) AF: 0.0733 AC: 2453 AN: 33480

American (AMR) AF: 0.00356 AC: 159 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.000215 AC: 239 AN: 1111988

Other (OTH) AF: 0.00434 AC: 262 AN: 60396

GnomAD4 genome AF: 0.0210 AC: 3193 AN: 152220 Hom.: 112 Cov.: 32 AF XY: 0.0204 AC XY: 1521 AN XY: 74428

African (AFR) AF: 0.0720 AC: 2990 AN: 41530

American (AMR) AF: 0.00981 AC: 150 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68000

Other (OTH) AF: 0.0166 AC: 35 AN: 2110

Alfa AF: 0.00724 Hom.: 75

Bravo AF: 0.0247

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0745 AC: 277

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00635 AC: 767

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Alport syndrome (2)
-	-	2	not provided (2)
-	-	1	Autosomal recessive Alport syndrome (1)
-	-	1	Kidney disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.4
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.10
Sift	Benign	0.43	T
Sift4G	Benign	0.41	T
Polyphen		0.0030	B
Vest4		0.24
MVP		0.58
MPC		0.50
ClinPred		0.022	T
GERP RS		2.0
Varity_R		0.094
gMVP		0.60
Mutation Taster		=98/2	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: rs35998949; hg19: chr2-227945181;