chr2-227204294-A-G

Variant names:

• chr2-227204294-A-G
• rs6756117
• NM_000091.5:c.88-33674A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000091.5(COL4A3):​c.88-33674A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.468 in 152,042 control chromosomes in the GnomAD database, including 17,677 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.47 (17677 hom., cov: 32)
• Consequence: COL4A3 NM_000091.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.753
• Publications: 6 publications found

Genes affected

COL4A3 (HGNC:2204): (collagen type IV alpha 3 chain) Type IV collagen, the major structural component of basement membranes, is a multimeric protein composed of 3 alpha subunits. These subunits are encoded by 6 different genes, alpha 1 through alpha 6, each of which can form a triple helix structure with 2 other subunits to form type IV collagen. This gene encodes alpha 3. In the Goodpasture syndrome, autoantibodies bind to the collagen molecules in the basement membranes of alveoli and glomeruli. The epitopes that elicit these autoantibodies are localized largely to the non-collagenous C-terminal domain of the protein. A specific kinase phosphorylates amino acids in this same C-terminal region and the expression of this kinase is upregulated during pathogenesis. This gene is also linked to an autosomal recessive form of Alport syndrome. The mutations contributing to this syndrome are also located within the exons that encode this C-terminal region. 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. [provided by RefSeq, Jun 2010]

COL4A3 Gene-Disease associations (from GenCC):

• Alport syndrome 3b, autosomal recessive

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: G2P
• autosomal recessive Alport syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Myriad Women’s Health, Orphanet
• Alport syndrome

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant Alport syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• hematuria, benign familial, 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.756 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.88-33674A>G		intron_variant	Intron 1 of 51	ENST00000396578.8	NP_000082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.88-33674A>G		intron_variant	Intron 1 of 51	1	NM_000091.5	ENSP00000379823.3

Frequencies

GnomAD3 genomes AF: 0.468 AC: 71075 AN: 151924 Hom.: 17654 Cov.: 32

Gnomad AFR AF: 0.584

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.520

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.776

Gnomad SAS AF: 0.595

Gnomad FIN AF: 0.287

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.388

Gnomad OTH AF: 0.482

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.468 AC: 71146 AN: 152042 Hom.: 17677 Cov.: 32 AF XY: 0.468 AC XY: 34788 AN XY: 74342

African (AFR) AF: 0.584 AC: 24223 AN: 41466

American (AMR) AF: 0.520 AC: 7946 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1350 AN: 3466

East Asian (EAS) AF: 0.776 AC: 4020 AN: 5178

South Asian (SAS) AF: 0.596 AC: 2872 AN: 4822

European-Finnish (FIN) AF: 0.287 AC: 3032 AN: 10582

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.388 AC: 26342 AN: 67942

Other (OTH) AF: 0.486 AC: 1027 AN: 2112

Alfa AF: 0.427 Hom.: 11883

Bravo AF: 0.488

Asia WGS AF: 0.650 AC: 2261 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.30
DANN	Benign	0.66
PhyloP100		-0.75
Mutation Taster		=100/0	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: rs6756117; hg19: chr2-228069010;