rs35467545

Positions:

chr2-227254745-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.736

Variant links:

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]

COL4A3 links:

MFF-DT (HGNC:41067): (MFF divergent transcript)

MFF-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
COL4A3	NM_000091.5 link	c.888+30G>A		intron_variant		ENST00000396578.8	NP_000082.2	Q01955-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8 link	c.888+30G>A		intron_variant		1	NM_000091.5	ENSP00000379823.3		Q01955-1

Frequencies

GnomAD3 genomes

AF:

0.0760

AC:

11558

AN:

152142

Hom.:

570

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0854

AC XY:

59052

AN XY:

691856

show subpopulations

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.:

AF XY:

0.0771

AC XY:

5739

AN XY:

74452

show subpopulations

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:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

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 28% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 26. Only high quality variants are reported. -

Autosomal recessive Alport syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over