rs2396449

Positions:

• chr2-227209085-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000091.5(COL4A3):​c.88-28883C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 152,144 control chromosomes in the GnomAD database, including 1,909 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 0.15 (1909 hom., cov: 33)
• Consequence: COL4A3 NM_000091.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.376

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.88-28883C>T		intron_variant		ENST00000396578.8	NP_000082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.88-28883C>T		intron_variant		1	NM_000091.5	ENSP00000379823.3

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23127 AN: 152026 Hom.: 1910 Cov.: 33

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.149

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

GnomAD4 genome AF: 0.152 AC: 23136 AN: 152144 Hom.: 1909 Cov.: 33 AF XY: 0.152 AC XY: 11328 AN XY: 74376

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.191

Gnomad4 ASJ AF: 0.161

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.127

Gnomad4 FIN AF: 0.177

Gnomad4 NFE AF: 0.143

Gnomad4 OTH AF: 0.146

Alfa AF: 0.151 Hom.: 209

Bravo AF: 0.152

Asia WGS AF: 0.0580 AC: 202 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.36
DANN	Benign	0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs2396449; hg19: chr2-228073801;