NM_000092.5:c.4091-36G>A

Variant names:

• chr2-227022209-C-T
• rs3752896
• NM_000092.5:c.4091-36G>A

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.4091-36G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 1,611,764 control chromosomes in the GnomAD database, including 153,701 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (13996 hom., cov: 32)
  • Exomes 𝑓: 0.43 (139705 hom.)
• Consequence: COL4A4 NM_000092.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.98
• 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: 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=-0.87).
• BP6: Variant 2-227022209-C-T is Benign according to our data. Variant chr2-227022209-C-T is described in ClinVar as Benign. ClinVar VariationId is 1184793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.533 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A4	NM_000092.5	MANE Select	c.4091-36G>A		intron	N/A	NP_000083.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A4	ENST00000396625.5	TSL:5 MANE Select	c.4091-36G>A		intron	N/A	ENSP00000379866.3

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64842 AN: 151828 Hom.: 13971 Cov.: 32

Gnomad AFR AF: 0.396

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.390

Gnomad SAS AF: 0.551

Gnomad FIN AF: 0.490

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.404

GnomAD2 exomes AF: 0.460 AC: 113799 AN: 247294 AF XY: 0.460

Gnomad AFR exome AF: 0.396

Gnomad AMR exome AF: 0.527

Gnomad ASJ exome AF: 0.507

Gnomad EAS exome AF: 0.396

Gnomad FIN exome AF: 0.496

Gnomad NFE exome AF: 0.421

Gnomad OTH exome AF: 0.449

GnomAD4 exome AF: 0.434 AC: 634123 AN: 1459818 Hom.: 139705 Cov.: 35 AF XY: 0.437 AC XY: 317267 AN XY: 726332

African (AFR) AF: 0.390 AC: 13035 AN: 33440

American (AMR) AF: 0.521 AC: 23286 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.515 AC: 13438 AN: 26112

East Asian (EAS) AF: 0.411 AC: 16294 AN: 39686

South Asian (SAS) AF: 0.559 AC: 48173 AN: 86230

European-Finnish (FIN) AF: 0.495 AC: 26349 AN: 53242

Middle Eastern (MID) AF: 0.386 AC: 2222 AN: 5760

European-Non Finnish (NFE) AF: 0.419 AC: 465183 AN: 1110302

Other (OTH) AF: 0.433 AC: 26143 AN: 60334

GnomAD4 genome AF: 0.427 AC: 64910 AN: 151946 Hom.: 13996 Cov.: 32 AF XY: 0.430 AC XY: 31956 AN XY: 74240

African (AFR) AF: 0.396 AC: 16418 AN: 41434

American (AMR) AF: 0.459 AC: 7020 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 1710 AN: 3468

East Asian (EAS) AF: 0.391 AC: 2014 AN: 5152

South Asian (SAS) AF: 0.550 AC: 2651 AN: 4816

European-Finnish (FIN) AF: 0.490 AC: 5160 AN: 10534

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.421 AC: 28608 AN: 67938

Other (OTH) AF: 0.399 AC: 844 AN: 2114

Alfa AF: 0.433 Hom.: 4985

Bravo AF: 0.424

Asia WGS AF: 0.469 AC: 1633 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.074
DANN	Benign	0.74
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3752896; hg19: chr2-227886925; COSMIC: COSV61629631;