2-227191954-C-T

Variant names:

• chr2-227191954-C-T
• rs6436661
• NM_000091.5:c.87+27141C>T

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+27141C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.86 in 152,180 control chromosomes in the GnomAD database, including 56,398 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 0.86 (56398 hom., cov: 31)
• Consequence: COL4A3 NM_000091.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.162
• Publications: 3 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.883 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000091.5. 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
	COL4A3	NM_000091.5	MANE Select	c.87+27141C>T		intron	N/A	NP_000082.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	ENST00000396578.8	TSL:1 MANE Select	c.87+27141C>T		intron	N/A	ENSP00000379823.3

Frequencies

GnomAD3 genomes AF: 0.860 AC: 130778 AN: 152062 Hom.: 56351 Cov.: 31

Gnomad AFR AF: 0.793

Gnomad AMI AF: 0.935

Gnomad AMR AF: 0.896

Gnomad ASJ AF: 0.830

Gnomad EAS AF: 0.841

Gnomad SAS AF: 0.904

Gnomad FIN AF: 0.910

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.884

Gnomad OTH AF: 0.867

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

GnomAD4 genome AF: 0.860 AC: 130884 AN: 152180 Hom.: 56398 Cov.: 31 AF XY: 0.862 AC XY: 64134 AN XY: 74402

African (AFR) AF: 0.794 AC: 32935 AN: 41504

American (AMR) AF: 0.896 AC: 13691 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.830 AC: 2880 AN: 3470

East Asian (EAS) AF: 0.842 AC: 4349 AN: 5168

South Asian (SAS) AF: 0.904 AC: 4363 AN: 4824

European-Finnish (FIN) AF: 0.910 AC: 9651 AN: 10608

Middle Eastern (MID) AF: 0.806 AC: 237 AN: 294

European-Non Finnish (NFE) AF: 0.884 AC: 60090 AN: 68006

Other (OTH) AF: 0.868 AC: 1835 AN: 2114

Alfa AF: 0.879 Hom.: 80511

Bravo AF: 0.854

Asia WGS AF: 0.876 AC: 3036 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.14
DANN	Benign	0.80
PhyloP100		-0.16
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: rs6436661; hg19: chr2-228056670;