2-227199464-A-G

Variant names:

• chr2-227199464-A-G
• rs10498214
• NM_000091.5:c.87+34651A>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.87+34651A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 152,166 control chromosomes in the GnomAD database, including 5,133 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 0.25 (5133 hom., cov: 33)
• Consequence: COL4A3 NM_000091.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.38
• Publications: 9 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=-0.99).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.87+34651A>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.87+34651A>G		intron_variant	Intron 1 of 51	1	NM_000091.5	ENSP00000379823.3

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37836 AN: 152048 Hom.: 5133 Cov.: 33

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.338

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.0234

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.347

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.218

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

GnomAD4 genome AF: 0.249 AC: 37854 AN: 152166 Hom.: 5133 Cov.: 33 AF XY: 0.248 AC XY: 18470 AN XY: 74402

African (AFR) AF: 0.190 AC: 7897 AN: 41508

American (AMR) AF: 0.240 AC: 3674 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 737 AN: 3466

East Asian (EAS) AF: 0.0235 AC: 122 AN: 5192

South Asian (SAS) AF: 0.172 AC: 832 AN: 4826

European-Finnish (FIN) AF: 0.347 AC: 3667 AN: 10580

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.296 AC: 20137 AN: 67994

Other (OTH) AF: 0.215 AC: 455 AN: 2116

Alfa AF: 0.275 Hom.: 25463

Bravo AF: 0.237

Asia WGS AF: 0.0920 AC: 320 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.024
DANN	Benign	0.47
PhyloP100		-1.4
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: rs10498214; hg19: chr2-228064180;