rs56243460

Positions:

• chr2-227270755-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The ENST00000396578.8(COL4A3):​c.1576-15T>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0397 in 1,611,610 control chromosomes in the GnomAD database, including 1,779 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (399 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1380 hom.)
• Consequence: COL4A3 ENST00000396578.8 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.08

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 -16 ACMG points.

• BP6: Variant 2-227270755-T-G is Benign according to our data. Variant chr2-227270755-T-G is described in ClinVar as [Benign]. Clinvar id is 254984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.1576-15T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000396578.8	NP_000082.2
MFF-DT	NR_102371.1	n.423-1986A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.1576-15T>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000091.5	ENSP00000379823	P1
MFF-DT	ENST00000439598.6	n.423-1986A>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0606 AC: 9212 AN: 152128 Hom.: 400 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0534

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0164

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0363

Gnomad OTH AF: 0.0497

GnomAD3 exomes AF: 0.0460 AC: 11456 AN: 249188 Hom.: 411 AF XY: 0.0424 AC XY: 5740 AN XY: 135246

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.0771

Gnomad ASJ exome AF: 0.0212

Gnomad EAS exome AF: 0.00251

Gnomad SAS exome AF: 0.0178

Gnomad FIN exome AF: 0.0986

Gnomad NFE exome AF: 0.0352

Gnomad OTH exome AF: 0.0374

GnomAD4 exome AF: 0.0376 AC: 54827 AN: 1459364 Hom.: 1380 Cov.: 30 AF XY: 0.0365 AC XY: 26541 AN XY: 726230

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.0743

Gnomad4 ASJ exome AF: 0.0193

Gnomad4 EAS exome AF: 0.00144

Gnomad4 SAS exome AF: 0.0184

Gnomad4 FIN exome AF: 0.0927

Gnomad4 NFE exome AF: 0.0347

Gnomad4 OTH exome AF: 0.0376

GnomAD4 genome AF: 0.0605 AC: 9217 AN: 152246 Hom.: 399 Cov.: 32 AF XY: 0.0624 AC XY: 4648 AN XY: 74436

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.0535

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.00232

Gnomad4 SAS AF: 0.0162

Gnomad4 FIN AF: 0.107

Gnomad4 NFE AF: 0.0363

Gnomad4 OTH AF: 0.0491

Alfa AF: 0.0405 Hom.: 40

Bravo AF: 0.0591

Asia WGS AF: 0.0150 AC: 53 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	c.1576-15T>G in intron 24 of COL4A3: This variant is not expected to have clinic al significance because it has been identified in 10.86% (1054/9706) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs56243460). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive Alport syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Alport syndrome Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.28		Position offset: 15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs56243460; hg19: chr2-228135471;