rs55928538

Positions:

• chr2-227256084-T-C

Variant summary

Our verdict is Benign. Variant got -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:6
• Conservation: PhyloP100: -0.0190

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

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 255009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227256084-T-C is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0507 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A3	NM_000091.5	c.933+14T>C		intron_variant		ENST00000396578.8
MFF-DT	NR_102371.1	n.1592+3094A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A3	ENST00000396578.8	c.933+14T>C		intron_variant		1	NM_000091.5	P1
MFF-DT	ENST00000439598.6	n.1592+3094A>G		intron_variant, non_coding_transcript_variant		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

GnomAD3 exomes AF: 0.0270 AC: 6739 AN: 249404 Hom.: 136 AF XY: 0.0286 AC XY: 3873 AN XY: 135318

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 SAS exome AF: 0.0282

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

Gnomad4 AFR exome AF: 0.00711

Gnomad4 AMR exome AF: 0.0198

Gnomad4 ASJ exome AF: 0.0737

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0290

Gnomad4 FIN exome AF: 0.0187

Gnomad4 NFE exome AF: 0.0337

Gnomad4 OTH exome AF: 0.0308

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

Gnomad4 AFR AF: 0.00810

Gnomad4 AMR AF: 0.0246

Gnomad4 ASJ AF: 0.0694

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0228

Gnomad4 FIN AF: 0.0183

Gnomad4 NFE AF: 0.0336

Gnomad4 OTH AF: 0.0407

Alfa AF: 0.0330 Hom.: 34

Bravo AF: 0.0238

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	c.933+14T>C in intron 16 of COL4A3: This variant is not expected to have clinica l significance because it is not located within the splice consensus sequence an d has been identified in 3.58% (2388/66624) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs55928538) . -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Autosomal recessive Alport syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Alport syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.3
DANN	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs55928538; hg19: chr2-228120800;