2-227237964-C-T

Position:

• chr2-227237964-C-T

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.88-4C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00441 in 1,608,052 control chromosomes in the GnomAD database, including 328 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (36 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (292 hom.)
• Consequence: COL4A3 NM_000091.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0004138
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0460

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=-0.55).
• BP6: Variant 2-227237964-C-T is Benign according to our data. Variant chr2-227237964-C-T is described in ClinVar as [Benign]. Clinvar id is 255008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227237964-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.88-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000396578.8	NP_000082.2
MFF-DT	NR_102371.1	n.1681+122G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.88-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000091.5	ENSP00000379823	P1
MFF-DT	ENST00000439598.6	n.1681+122G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00771 AC: 1172 AN: 152072 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0594

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.0200

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00719

GnomAD3 exomes AF: 0.0171 AC: 4275 AN: 249508 Hom.: 243 AF XY: 0.0131 AC XY: 1774 AN XY: 135354

Gnomad AFR exome AF: 0.00245

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.0226

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.00406 AC: 5912 AN: 1455862 Hom.: 292 Cov.: 27 AF XY: 0.00358 AC XY: 2597 AN XY: 724672

Gnomad4 AFR exome AF: 0.00132

Gnomad4 AMR exome AF: 0.0999

Gnomad4 ASJ exome AF: 0.00185

Gnomad4 EAS exome AF: 0.0233

Gnomad4 SAS exome AF: 0.000847

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.00387

GnomAD4 genome AF: 0.00771 AC: 1174 AN: 152190 Hom.: 36 Cov.: 32 AF XY: 0.00862 AC XY: 641 AN XY: 74398

Gnomad4 AFR AF: 0.00255

Gnomad4 AMR AF: 0.0595

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.0199

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00712

Alfa AF: 0.00212 Hom.: 4

Bravo AF: 0.0136

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	c.88-4C>T in intron 1 of COL4A3: This variant is not expected to have clinical s ignificance because it is not located within the splice consensus sequence and h as been identified in 11.92% (1380/11576) of Latino chromosomes by the Exome Agg regation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs148393022). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Sep 20, 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 29, 2018	Variant summary: COL4A3 c.88-4C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.016 in 277078 control chromosomes, predominantly at a frequency of 0.11 within the Latino subpopulation in the gnomAD database, including 235 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 54-fold of the estimated maximal expected allele frequency for a pathogenic variant in COL4A3 causing autosomal recessive Alport Syndrome (0.002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.88-4C>T in individuals affected with autosomal recessive Alport Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (3x) /likely benign (1x). Based on the evidence outlined above, the variant was classified as benign. -

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. -

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	-	- -

Focal segmental glomerulosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 02, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	8.9
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00041
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.010		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: rs148393022; hg19: chr2-228102680;