2-227248459-A-G

Position:

• chr2-227248459-A-G

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.485A>G​(p.Glu162Gly) 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 1,609,424 control chromosomes in the GnomAD database, including 560,380 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E162E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.78 (46870 hom., cov: 30)
  • Exomes 𝑓: 0.84 (513510 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.228

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 (MetaRNN=1.2934814E-6).
• BP6: Variant 2-227248459-A-G is Benign according to our data. Variant chr2-227248459-A-G is described in ClinVar as [Benign]. Clinvar id is 255001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227248459-A-G is described in Lovd as [Benign]. Variant chr2-227248459-A-G is described in Lovd as [Likely_benign].
• 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/exons	MANE	UniProt
COL4A3	NM_000091.5	c.485A>G	p.Glu162Gly	missense_variant	9/52	ENST00000396578.8
MFF-DT	NR_102371.1	n.1593-10285T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A3	ENST00000396578.8	c.485A>G	p.Glu162Gly	missense_variant	9/52	1	NM_000091.5	P1
MFF-DT	ENST00000439598.6	n.1593-10285T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.780 AC: 118480 AN: 151958 Hom.: 46841 Cov.: 30

Gnomad AFR AF: 0.626

Gnomad AMI AF: 0.790

Gnomad AMR AF: 0.847

Gnomad ASJ AF: 0.778

Gnomad EAS AF: 0.907

Gnomad SAS AF: 0.860

Gnomad FIN AF: 0.819

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.837

Gnomad OTH AF: 0.776

GnomAD3 exomes AF: 0.835 AC: 208114 AN: 249350 Hom.: 87492 AF XY: 0.837 AC XY: 113200 AN XY: 135304

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 SAS exome AF: 0.857

Gnomad FIN exome AF: 0.825

Gnomad NFE exome AF: 0.835

Gnomad OTH exome AF: 0.822

GnomAD4 exome AF: 0.838 AC: 1221628 AN: 1457348 Hom.: 513510 Cov.: 33 AF XY: 0.838 AC XY: 607873 AN XY: 725274

Gnomad4 AFR exome AF: 0.622

Gnomad4 AMR exome AF: 0.881

Gnomad4 ASJ exome AF: 0.775

Gnomad4 EAS exome AF: 0.890

Gnomad4 SAS exome AF: 0.857

Gnomad4 FIN exome AF: 0.826

Gnomad4 NFE exome AF: 0.843

Gnomad4 OTH exome AF: 0.826

GnomAD4 genome AF: 0.780 AC: 118560 AN: 152076 Hom.: 46870 Cov.: 30 AF XY: 0.781 AC XY: 58037 AN XY: 74358

Gnomad4 AFR AF: 0.626

Gnomad4 AMR AF: 0.847

Gnomad4 ASJ AF: 0.778

Gnomad4 EAS AF: 0.907

Gnomad4 SAS AF: 0.861

Gnomad4 FIN AF: 0.819

Gnomad4 NFE AF: 0.837

Gnomad4 OTH AF: 0.775

Alfa AF: 0.826 Hom.: 128506

Bravo AF: 0.775

TwinsUK AF: 0.829 AC: 3075

ALSPAC AF: 0.846 AC: 3260

ESP6500AA AF: 0.640 AC: 2326

ESP6500EA AF: 0.828 AC: 6760

ExAC AF: 0.830 AC: 100265

Asia WGS AF: 0.848 AC: 2948 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

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Glu162Gly in exon 9 of COL4A3: This variant is not expected to have clinical s ignificance because it has been identified in 91.38% (7859/8600) of East Asian c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs6436669). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 99% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 92. Only high quality variants are reported. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Alport syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 recessive Alport syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Autosomal dominant Alport syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	13
DANN	Benign	0.54
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.16
Sift	Benign	0.83	T
Sift4G	Benign	0.42	T
Polyphen		0.019	B
Vest4		0.065
MPC		0.23
ClinPred		0.0032	T
GERP RS		1.2
Varity_R		0.033
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs6436669; hg19: chr2-228113175;