rs13386404

Variant names:

• chr2-227254194-A-G
• rs13386404
• NM_000091.5:c.828+20A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000091.5(COL4A3):​c.828+20A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0462 in 1,603,438 control chromosomes in the GnomAD database, including 5,152 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (2264 hom., cov: 32)
  • Exomes 𝑓: 0.039 (2888 hom.)
• Consequence: COL4A3 NM_000091.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.66
• Publications: 7 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]

MFF-DT (HGNC:41067): (MFF divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-227254194-A-G is Benign according to our data. Variant chr2-227254194-A-G is described in ClinVar as Benign. ClinVar VariationId is 255007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.321 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	NM_000091.5	MANE Select	c.828+20A>G		intron	N/A	NP_000082.2	Q01955-1
	MFF-DT	NR_102371.1		n.1592+4984T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	ENST00000396578.8	TSL:1 MANE Select	c.828+20A>G		intron	N/A	ENSP00000379823.3	Q01955-1
	MFF-DT	ENST00000439598.6	TSL:1	n.1592+4984T>C		intron	N/A
	COL4A3	ENST00000871618.1		c.828+20A>G		intron	N/A	ENSP00000541677.1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17979 AN: 151864 Hom.: 2249 Cov.: 32

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0552

Gnomad ASJ AF: 0.0752

Gnomad EAS AF: 0.0680

Gnomad SAS AF: 0.0433

Gnomad FIN AF: 0.0661

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.0290

Gnomad OTH AF: 0.0844

GnomAD2 exomes AF: 0.0580 AC: 14441 AN: 249070 AF XY: 0.0521

Gnomad AFR exome AF: 0.333

Gnomad AMR exome AF: 0.0358

Gnomad ASJ exome AF: 0.0772

Gnomad EAS exome AF: 0.0673

Gnomad FIN exome AF: 0.0626

Gnomad NFE exome AF: 0.0292

Gnomad OTH exome AF: 0.0530

GnomAD4 exome AF: 0.0387 AC: 56114 AN: 1451462 Hom.: 2888 Cov.: 29 AF XY: 0.0376 AC XY: 27211 AN XY: 722890

African (AFR) AF: 0.331 AC: 10919 AN: 33014

American (AMR) AF: 0.0380 AC: 1699 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0767 AC: 1996 AN: 26026

East Asian (EAS) AF: 0.103 AC: 4090 AN: 39586

South Asian (SAS) AF: 0.0367 AC: 3157 AN: 86050

European-Finnish (FIN) AF: 0.0560 AC: 2991 AN: 53386

Middle Eastern (MID) AF: 0.0708 AC: 406 AN: 5738

European-Non Finnish (NFE) AF: 0.0251 AC: 27697 AN: 1102980

Other (OTH) AF: 0.0527 AC: 3159 AN: 59994

GnomAD4 genome AF: 0.119 AC: 18025 AN: 151976 Hom.: 2264 Cov.: 32 AF XY: 0.118 AC XY: 8729 AN XY: 74272

African (AFR) AF: 0.326 AC: 13503 AN: 41416

American (AMR) AF: 0.0551 AC: 842 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0752 AC: 261 AN: 3470

East Asian (EAS) AF: 0.0684 AC: 354 AN: 5176

South Asian (SAS) AF: 0.0423 AC: 204 AN: 4826

European-Finnish (FIN) AF: 0.0661 AC: 696 AN: 10526

Middle Eastern (MID) AF: 0.0514 AC: 15 AN: 292

European-Non Finnish (NFE) AF: 0.0290 AC: 1969 AN: 67980

Other (OTH) AF: 0.0835 AC: 176 AN: 2108

Alfa AF: 0.0782 Hom.: 348

Bravo AF: 0.127

Asia WGS AF: 0.0690 AC: 242 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Autosomal recessive Alport syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.024
DANN	Benign	0.60
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.040		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: rs13386404; hg19: chr2-228118910; COSMIC: COSV67415786;