2-227246719-T-C

Variant names:

• chr2-227246719-T-C
• rs10178458
• NM_000091.5:c.422T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000091.5(COL4A3):​c.422T>C​(p.Leu141Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.833 in 1,610,764 control chromosomes in the GnomAD database, including 560,578 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.78 (46853 hom., cov: 30)
  • Exomes 𝑓: 0.84 (513725 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.487
• Publications: 60 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 -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000091.5
• BP4: Computational evidence support a benign effect (MetaRNN=4.154798E-6).
• BP6: Variant 2-227246719-T-C is Benign according to our data. Variant chr2-227246719-T-C is described in ClinVar as Benign. ClinVar VariationId is 254996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.885 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.422T>C	p.Leu141Pro	missense_variant	Exon 7 of 52	ENST00000396578.8	NP_000082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.422T>C	p.Leu141Pro	missense_variant	Exon 7 of 52	1	NM_000091.5	ENSP00000379823.3

Frequencies

GnomAD3 genomes AF: 0.780 AC: 118416 AN: 151884 Hom.: 46823 Cov.: 30

Gnomad AFR AF: 0.626

Gnomad AMI AF: 0.791

Gnomad AMR AF: 0.847

Gnomad ASJ AF: 0.779

Gnomad EAS AF: 0.907

Gnomad SAS AF: 0.861

Gnomad FIN AF: 0.818

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.837

Gnomad OTH AF: 0.777

GnomAD2 exomes AF: 0.834 AC: 207949 AN: 249198 AF XY: 0.836

Gnomad AFR exome AF: 0.628

Gnomad AMR exome AF: 0.887

Gnomad ASJ exome AF: 0.775

Gnomad EAS exome AF: 0.919

Gnomad FIN exome AF: 0.825

Gnomad NFE exome AF: 0.835

Gnomad OTH exome AF: 0.822

GnomAD4 exome AF: 0.838 AC: 1222544 AN: 1458760 Hom.: 513725 Cov.: 39 AF XY: 0.838 AC XY: 608237 AN XY: 725874

African (AFR) AF: 0.622 AC: 20751 AN: 33356

American (AMR) AF: 0.881 AC: 39344 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.775 AC: 20213 AN: 26086

East Asian (EAS) AF: 0.890 AC: 35293 AN: 39660

South Asian (SAS) AF: 0.857 AC: 73890 AN: 86202

European-Finnish (FIN) AF: 0.826 AC: 44081 AN: 53396

Middle Eastern (MID) AF: 0.712 AC: 4106 AN: 5766

European-Non Finnish (NFE) AF: 0.843 AC: 935084 AN: 1109350

Other (OTH) AF: 0.826 AC: 49782 AN: 60264

GnomAD4 genome AF: 0.780 AC: 118499 AN: 152004 Hom.: 46853 Cov.: 30 AF XY: 0.780 AC XY: 57977 AN XY: 74302

African (AFR) AF: 0.626 AC: 25941 AN: 41432

American (AMR) AF: 0.847 AC: 12931 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.779 AC: 2701 AN: 3468

East Asian (EAS) AF: 0.907 AC: 4688 AN: 5168

South Asian (SAS) AF: 0.861 AC: 4150 AN: 4818

European-Finnish (FIN) AF: 0.818 AC: 8647 AN: 10570

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.837 AC: 56897 AN: 67972

Other (OTH) AF: 0.776 AC: 1639 AN: 2112

Alfa AF: 0.820 Hom.: 236058

Bravo AF: 0.775

TwinsUK AF: 0.829 AC: 3075

ALSPAC AF: 0.846 AC: 3260

ESP6500AA AF: 0.643 AC: 2369

ESP6500EA AF: 0.828 AC: 6759

ExAC AF: 0.830 AC: 100213

Asia WGS AF: 0.847 AC: 2947 AN: 3478

EpiCase AF: 0.823

EpiControl AF: 0.829

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Apr 28, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Leu141Pro in exon 7 of COL4A3: This variant is not expected to have clinical s ignificance because it has been identified in 91.36% (7855/8598) of East Asian c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs10178458). -

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 95% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 88. Only high quality variants are reported. -

Autosomal recessive Alport syndrome Benign:2

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alport syndrome Benign:2

Jan 13, 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. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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
AlphaMissense	Benign	0.038
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	2.1
DANN	Benign	0.56
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0032	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0000042	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.4	N
PhyloP100		0.49
PrimateAI	Benign	0.37	T
PROVEAN	Benign	2.9	N
REVEL	Benign	0.26
Sift	Benign	1.0	T
Sift4G	Benign	0.64	T
Polyphen		0.042	B
Vest4		0.042
MPC		0.31
ClinPred		0.0010	T
GERP RS		3.6
Varity_R		0.044
gMVP		0.16
Mutation Taster		=95/5	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: rs10178458; hg19: chr2-228111435; COSMIC: COSV107512072;