rs77431913

chr2-227254099-G-A

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.766-13G>A 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 0.0124 in 1,612,466 control chromosomes in the GnomAD database, including 915 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (197 hom., cov: 32)
  • Exomes 𝑓: 0.010 (718 hom.)
• Consequence: COL4A3 NM_000091.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.120

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=-0.5).
• BP6: Variant 2-227254099-G-A is Benign according to our data. Variant chr2-227254099-G-A is described in ClinVar as [Benign]. Clinvar id is 255005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227254099-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A3	NM_000091.5	c.766-13G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000396578.8
MFF-DT	NR_102371.1	n.1592+5079C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A3	ENST00000396578.8	c.766-13G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000091.5	P1
MFF-DT	ENST00000439598.6	n.1592+5079C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0304 AC: 4624 AN: 152082 Hom.: 196 Cov.: 32

Gnomad AFR AF: 0.0685

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.0270

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00291

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.0249 AC: 6207 AN: 249190 Hom.: 361 AF XY: 0.0229 AC XY: 3100 AN XY: 135184

Gnomad AFR exome AF: 0.0703

Gnomad AMR exome AF: 0.00733

Gnomad ASJ exome AF: 0.00408

Gnomad EAS exome AF: 0.181

Gnomad SAS exome AF: 0.0165

Gnomad FIN exome AF: 0.0277

Gnomad NFE exome AF: 0.00320

Gnomad OTH exome AF: 0.0185

GnomAD4 exome AF: 0.0105 AC: 15287 AN: 1460266 Hom.: 718 Cov.: 31 AF XY: 0.0104 AC XY: 7565 AN XY: 726550

Gnomad4 AFR exome AF: 0.0709

Gnomad4 AMR exome AF: 0.00796

Gnomad4 ASJ exome AF: 0.00475

Gnomad4 EAS exome AF: 0.168

Gnomad4 SAS exome AF: 0.0154

Gnomad4 FIN exome AF: 0.0252

Gnomad4 NFE exome AF: 0.00161

Gnomad4 OTH exome AF: 0.0203

GnomAD4 genome AF: 0.0304 AC: 4627 AN: 152200 Hom.: 197 Cov.: 32 AF XY: 0.0318 AC XY: 2365 AN XY: 74392

Gnomad4 AFR AF: 0.0685

Gnomad4 AMR AF: 0.0147

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.170

Gnomad4 SAS AF: 0.0261

Gnomad4 FIN AF: 0.0270

Gnomad4 NFE AF: 0.00290

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0155 Hom.: 23

Bravo AF: 0.0322

Asia WGS AF: 0.103 AC: 358 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	c.766-13G>A in intron 13 of COL4A3: This variant is not expected to have clinica l significance because it has been identified in 18.09% (1554/8590) of East Asia n chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org; dbSNP rs77431913). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2018	- -

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	-0.50
Cadd	Benign	2.9
Dann	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs77431913; hg19: chr2-228118815;