rs35467545

chr2-227254745-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.888+30G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0839 in 1,533,476 control chromosomes in the GnomAD database, including 6,046 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (575 hom., cov: 32)
  • Exomes 𝑓: 0.085 (5471 hom.)
• Consequence: COL4A3 NM_000091.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.736

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=-0.9).
• BP6: Variant 2-227254745-G-A is Benign according to our data. Variant chr2-227254745-G-A is described in ClinVar as [Benign]. Clinvar id is 682614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227254745-G-A is described in Lovd as [Likely_benign]. Variant chr2-227254745-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) 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.888+30G>A		intron_variant		ENST00000396578.8
MFF-DT	NR_102371.1	n.1592+4433C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A3	ENST00000396578.8	c.888+30G>A		intron_variant		1	NM_000091.5	P1
MFF-DT	ENST00000439598.6	n.1592+4433C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0760 AC: 11558 AN: 152142 Hom.: 570 Cov.: 32

Gnomad AFR AF: 0.0335

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.155

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.0380

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0786

Gnomad OTH AF: 0.0908

GnomAD3 exomes AF: 0.0971 AC: 24158 AN: 248786 Hom.: 1437 AF XY: 0.0968 AC XY: 13064 AN XY: 134958

Gnomad AFR exome AF: 0.0338

Gnomad AMR exome AF: 0.172

Gnomad ASJ exome AF: 0.0944

Gnomad EAS exome AF: 0.154

Gnomad SAS exome AF: 0.111

Gnomad FIN exome AF: 0.0370

Gnomad NFE exome AF: 0.0817

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.0848 AC: 117108 AN: 1381216 Hom.: 5471 Cov.: 23 AF XY: 0.0854 AC XY: 59052 AN XY: 691856

Gnomad4 AFR exome AF: 0.0325

Gnomad4 AMR exome AF: 0.172

Gnomad4 ASJ exome AF: 0.0963

Gnomad4 EAS exome AF: 0.124

Gnomad4 SAS exome AF: 0.110

Gnomad4 FIN exome AF: 0.0419

Gnomad4 NFE exome AF: 0.0803

Gnomad4 OTH exome AF: 0.0950

GnomAD4 genome AF: 0.0760 AC: 11578 AN: 152260 Hom.: 575 Cov.: 32 AF XY: 0.0771 AC XY: 5739 AN XY: 74452

Gnomad4 AFR AF: 0.0335

Gnomad4 AMR AF: 0.165

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.155

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.0380

Gnomad4 NFE AF: 0.0786

Gnomad4 OTH AF: 0.0937

Alfa AF: 0.0819 Hom.: 225

Bravo AF: 0.0841

Asia WGS AF: 0.143 AC: 497 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive Alport syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.28
Dann	Benign	0.39

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: rs35467545; hg19: chr2-228119461;