2-227263824-C-T

Position:

• chr2-227263824-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000091.5(COL4A3):​c.1195C>T​(p.Leu399=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.751 in 1,613,536 control chromosomes in the GnomAD database, including 456,799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (40860 hom., cov: 32)
  • Exomes 𝑓: 0.75 (415939 hom.)
• Consequence: COL4A3 NM_000091.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.664

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 2-227263824-C-T is Benign according to our data. Variant chr2-227263824-C-T is described in ClinVar as [Benign]. Clinvar id is 254976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227263824-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.664 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.856 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.1195C>T	p.Leu399=	synonymous_variant	21/52	ENST00000396578.8	NP_000082.2
MFF-DT	NR_102371.1	n.1486+845G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.1195C>T	p.Leu399=	synonymous_variant	21/52	1	NM_000091.5	ENSP00000379823	P1
MFF-DT	ENST00000439598.6	n.1486+845G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.732 AC: 111237 AN: 151988 Hom.: 40817 Cov.: 32

Gnomad AFR AF: 0.673

Gnomad AMI AF: 0.574

Gnomad AMR AF: 0.769

Gnomad ASJ AF: 0.638

Gnomad EAS AF: 0.878

Gnomad SAS AF: 0.817

Gnomad FIN AF: 0.800

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.741

Gnomad OTH AF: 0.686

GnomAD3 exomes AF: 0.768 AC: 191130 AN: 248780 Hom.: 74190 AF XY: 0.766 AC XY: 103411 AN XY: 135050

Gnomad AFR exome AF: 0.670

Gnomad AMR exome AF: 0.846

Gnomad ASJ exome AF: 0.637

Gnomad EAS exome AF: 0.884

Gnomad SAS exome AF: 0.807

Gnomad FIN exome AF: 0.798

Gnomad NFE exome AF: 0.737

Gnomad OTH exome AF: 0.744

GnomAD4 exome AF: 0.753 AC: 1100520 AN: 1461430 Hom.: 415939 Cov.: 48 AF XY: 0.753 AC XY: 547225 AN XY: 727030

Gnomad4 AFR exome AF: 0.667

Gnomad4 AMR exome AF: 0.837

Gnomad4 ASJ exome AF: 0.642

Gnomad4 EAS exome AF: 0.868

Gnomad4 SAS exome AF: 0.806

Gnomad4 FIN exome AF: 0.795

Gnomad4 NFE exome AF: 0.745

Gnomad4 OTH exome AF: 0.750

GnomAD4 genome AF: 0.732 AC: 111337 AN: 152106 Hom.: 40860 Cov.: 32 AF XY: 0.736 AC XY: 54731 AN XY: 74364

Gnomad4 AFR AF: 0.673

Gnomad4 AMR AF: 0.769

Gnomad4 ASJ AF: 0.638

Gnomad4 EAS AF: 0.878

Gnomad4 SAS AF: 0.816

Gnomad4 FIN AF: 0.800

Gnomad4 NFE AF: 0.741

Gnomad4 OTH AF: 0.685

Alfa AF: 0.720 Hom.: 18021

Bravo AF: 0.726

Asia WGS AF: 0.808 AC: 2813 AN: 3478

EpiCase AF: 0.713

EpiControl AF: 0.718

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Leu399Leu in exon 21 of COL4A3: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 89.00% (7590/8528) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs10205042). -
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	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 92% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 86. Only high quality variants are reported. -

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 12, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive Alport syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Autosomal recessive Alport syndrome;C5882663:Autosomal dominant Alport syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 28, 2017

- -

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
BayesDel_noAF	Benign	-0.64
CADD	Benign	1.9
DANN	Benign	0.76

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: rs10205042; hg19: chr2-228128540;