NM_000091.5:c.144+12C>A

Variant names:

• chr2-227238036-C-A
• rs1882435
• NM_000091.5:c.144+12C>A

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.144+12C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 1,560,592 control chromosomes in the GnomAD database, including 68,835 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6605 hom., cov: 32)
  • Exomes 𝑓: 0.29 (62230 hom.)
• Consequence: COL4A3 NM_000091.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.560
• Publications: 22 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=-0.88).
• BP6: Variant 2-227238036-C-A is Benign according to our data. Variant chr2-227238036-C-A is described in ClinVar as Benign. ClinVar VariationId is 254981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.144+12C>A		intron_variant	Intron 2 of 51	ENST00000396578.8	NP_000082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.144+12C>A		intron_variant	Intron 2 of 51	1	NM_000091.5	ENSP00000379823.3

Frequencies

GnomAD3 genomes AF: 0.293 AC: 44436 AN: 151904 Hom.: 6598 Cov.: 32

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.428

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.301

GnomAD2 exomes AF: 0.310 AC: 77221 AN: 249472 AF XY: 0.308

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.312

Gnomad ASJ exome AF: 0.323

Gnomad EAS exome AF: 0.458

Gnomad FIN exome AF: 0.281

Gnomad NFE exome AF: 0.301

Gnomad OTH exome AF: 0.310

GnomAD4 exome AF: 0.294 AC: 414371 AN: 1408570 Hom.: 62230 Cov.: 23 AF XY: 0.295 AC XY: 207388 AN XY: 703904

African (AFR) AF: 0.260 AC: 8405 AN: 32352

American (AMR) AF: 0.308 AC: 13745 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 8125 AN: 25762

East Asian (EAS) AF: 0.407 AC: 16034 AN: 39400

South Asian (SAS) AF: 0.293 AC: 25022 AN: 85328

European-Finnish (FIN) AF: 0.282 AC: 15003 AN: 53178

Middle Eastern (MID) AF: 0.326 AC: 1849 AN: 5666

European-Non Finnish (NFE) AF: 0.290 AC: 308389 AN: 1063668

Other (OTH) AF: 0.304 AC: 17799 AN: 58604

GnomAD4 genome AF: 0.292 AC: 44462 AN: 152022 Hom.: 6605 Cov.: 32 AF XY: 0.293 AC XY: 21789 AN XY: 74314

African (AFR) AF: 0.261 AC: 10815 AN: 41470

American (AMR) AF: 0.312 AC: 4763 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 1074 AN: 3468

East Asian (EAS) AF: 0.429 AC: 2212 AN: 5162

South Asian (SAS) AF: 0.277 AC: 1336 AN: 4818

European-Finnish (FIN) AF: 0.275 AC: 2902 AN: 10552

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.302 AC: 20499 AN: 67960

Other (OTH) AF: 0.302 AC: 636 AN: 2108

Alfa AF: 0.307 Hom.: 9759

Bravo AF: 0.296

Asia WGS AF: 0.336 AC: 1168 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.144+12C>A in intron 2 of COL4A3: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence and has been identified in 45.37% (3907/8612) of East Asian chromosomes by the Exom e Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1882435) .

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 45% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 42. Only high quality variants are reported.

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Autosomal recessive Alport syndrome Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Alport syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Autosomal dominant Alport syndrome Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.62
DANN	Benign	0.61
PhyloP100		-0.56
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1882435; hg19: chr2-228102752; COSMIC: COSV67414037; COSMIC: COSV67414037;