rs2228558

Variant names:

• chr2-227147485-G-A
• rs2228558
• NM_000092.5:c.-2C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000092.5(COL4A4):​c.-2C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,612,518 control chromosomes in the GnomAD database, including 4,284 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.095 (2209 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (2075 hom.)
• Consequence: COL4A4 NM_000092.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.433
• Publications: 4 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Orphanet, Ambry Genetics, Myriad Women’s Health
• Alport syndrome

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-227147485-G-A is Benign according to our data. Variant chr2-227147485-G-A is described in ClinVar as Benign. ClinVar VariationId is 255011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.324 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.-2C>T		5_prime_UTR	Exon 2 of 48	NP_000083.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A4	ENST00000396625.5	TSL:5 MANE Select	c.-2C>T		5_prime_UTR	Exon 2 of 48	ENSP00000379866.3
	COL4A4	ENST00000643379.1		c.-2C>T		5_prime_UTR	Exon 2 of 15	ENSP00000494516.1
	COL4A4	ENST00000683508.1		c.-2C>T		5_prime_UTR	Exon 1 of 2	ENSP00000506932.1

Frequencies

GnomAD3 genomes AF: 0.0946 AC: 14375 AN: 152028 Hom.: 2203 Cov.: 32

Gnomad AFR AF: 0.329

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0350

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.0607

GnomAD2 exomes AF: 0.0244 AC: 6081 AN: 249360 AF XY: 0.0192

Gnomad AFR exome AF: 0.338

Gnomad AMR exome AF: 0.0157

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000989

Gnomad OTH exome AF: 0.0102

GnomAD4 exome AF: 0.00985 AC: 14382 AN: 1460372 Hom.: 2075 Cov.: 30 AF XY: 0.00868 AC XY: 6307 AN XY: 726592

African (AFR) AF: 0.339 AC: 11204 AN: 33004

American (AMR) AF: 0.0169 AC: 755 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26116

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39672

South Asian (SAS) AF: 0.00436 AC: 376 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.0220 AC: 127 AN: 5760

European-Non Finnish (NFE) AF: 0.000558 AC: 620 AN: 1111288

Other (OTH) AF: 0.0213 AC: 1286 AN: 60282

GnomAD4 genome AF: 0.0947 AC: 14409 AN: 152146 Hom.: 2209 Cov.: 32 AF XY: 0.0913 AC XY: 6794 AN XY: 74390

African (AFR) AF: 0.329 AC: 13632 AN: 41444

American (AMR) AF: 0.0349 AC: 533 AN: 15274

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

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

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00129 AC: 88 AN: 68028

Other (OTH) AF: 0.0601 AC: 127 AN: 2114

Alfa AF: 0.0467 Hom.: 768

Bravo AF: 0.108

Asia WGS AF: 0.0290 AC: 101 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00154

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Alport syndrome (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.5
DANN	Benign	0.39
PhyloP100		-0.43
PromoterAI		-0.029	Neutral
Mutation Taster		=299/1	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: rs2228558; hg19: chr2-228012201;