chr2-227256084-T-C

Variant names:

• chr2-227256084-T-C
• rs55928538
• NM_000091.5:c.933+14T>C

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.933+14T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0309 in 1,612,948 control chromosomes in the GnomAD database, including 868 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (54 hom., cov: 33)
  • Exomes 𝑓: 0.032 (814 hom.)
• Consequence: COL4A3 NM_000091.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0190
• 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=-0.83).
• BP6: Variant 2-227256084-T-C is Benign according to our data. Variant chr2-227256084-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0507 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.933+14T>C		intron	N/A	NP_000082.2	Q01955-1
	MFF-DT	NR_102371.1		n.1592+3094A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	ENST00000396578.8	TSL:1 MANE Select	c.933+14T>C		intron	N/A	ENSP00000379823.3	Q01955-1
	MFF-DT	ENST00000439598.6	TSL:1	n.1592+3094A>G		intron	N/A
	COL4A3	ENST00000871618.1		c.933+14T>C		intron	N/A	ENSP00000541677.1

Frequencies

GnomAD3 genomes AF: 0.0242 AC: 3678 AN: 152210 Hom.: 54 Cov.: 33

Gnomad AFR AF: 0.00813

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0246

Gnomad ASJ AF: 0.0694

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0336

Gnomad OTH AF: 0.0411

GnomAD2 exomes AF: 0.0270 AC: 6739 AN: 249404 AF XY: 0.0286

Gnomad AFR exome AF: 0.00794

Gnomad AMR exome AF: 0.0196

Gnomad ASJ exome AF: 0.0719

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0189

Gnomad NFE exome AF: 0.0330

Gnomad OTH exome AF: 0.0345

GnomAD4 exome AF: 0.0316 AC: 46118 AN: 1460620 Hom.: 814 Cov.: 30 AF XY: 0.0318 AC XY: 23107 AN XY: 726718

African (AFR) AF: 0.00711 AC: 238 AN: 33460

American (AMR) AF: 0.0198 AC: 886 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0737 AC: 1926 AN: 26118

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39674

South Asian (SAS) AF: 0.0290 AC: 2498 AN: 86218

European-Finnish (FIN) AF: 0.0187 AC: 998 AN: 53404

Middle Eastern (MID) AF: 0.0557 AC: 321 AN: 5762

European-Non Finnish (NFE) AF: 0.0337 AC: 37387 AN: 1110916

Other (OTH) AF: 0.0308 AC: 1857 AN: 60358

GnomAD4 genome AF: 0.0241 AC: 3678 AN: 152328 Hom.: 54 Cov.: 33 AF XY: 0.0240 AC XY: 1784 AN XY: 74488

African (AFR) AF: 0.00810 AC: 337 AN: 41586

American (AMR) AF: 0.0246 AC: 376 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0694 AC: 241 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0228 AC: 110 AN: 4822

European-Finnish (FIN) AF: 0.0183 AC: 194 AN: 10626

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0336 AC: 2288 AN: 68028

Other (OTH) AF: 0.0407 AC: 86 AN: 2114

Alfa AF: 0.0255 Hom.: 45

Bravo AF: 0.0238

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Alport syndrome (1)
-	-	1	Autosomal recessive Alport syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.3
DANN	Benign	0.75
PhyloP100		-0.019
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs55928538; hg19: chr2-228120800;