rs57611801

chr2-227298737-C-Achr2-227298737-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.3807C>A(p.Asp1269Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0389 in 1,613,962 control chromosomes in the GnomAD database, including 1,671 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. D1269D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.057 (339 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1332 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.256

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 (MetaRNN=0.0020103753).
• BP6: Variant 2-227298737-C-A is Benign according to our data. Variant chr2-227298737-C-A is described in ClinVar as [Benign]. Clinvar id is 254995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227298737-C-A is described in Lovd as [Benign]. Variant chr2-227298737-C-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0951 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A3	NM_000091.5	c.3807C>A	p.Asp1269Glu	missense_variant	43/52	ENST00000396578.8
MFF-DT	NR_102371.1	n.243+6723G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A3	ENST00000396578.8	c.3807C>A	p.Asp1269Glu	missense_variant	43/52	1	NM_000091.5	P1
MFF-DT	ENST00000439598.6	n.243+6723G>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0574 AC: 8726 AN: 152102 Hom.: 340 Cov.: 32

Gnomad AFR AF: 0.0978

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0523

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0165

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0359

Gnomad OTH AF: 0.0474

GnomAD3 exomes AF: 0.0449 AC: 11209 AN: 249456 Hom.: 395 AF XY: 0.0417 AC XY: 5645 AN XY: 135354

Gnomad AFR exome AF: 0.0982

Gnomad AMR exome AF: 0.0760

Gnomad ASJ exome AF: 0.0214

Gnomad EAS exome AF: 0.00250

Gnomad SAS exome AF: 0.0177

Gnomad FIN exome AF: 0.0974

Gnomad NFE exome AF: 0.0348

Gnomad OTH exome AF: 0.0363

GnomAD4 exome AF: 0.0370 AC: 54112 AN: 1461742 Hom.: 1332 Cov.: 31 AF XY: 0.0361 AC XY: 26219 AN XY: 727164

Gnomad4 AFR exome AF: 0.0959

Gnomad4 AMR exome AF: 0.0732

Gnomad4 ASJ exome AF: 0.0194

Gnomad4 EAS exome AF: 0.00141

Gnomad4 SAS exome AF: 0.0184

Gnomad4 FIN exome AF: 0.0916

Gnomad4 NFE exome AF: 0.0344

Gnomad4 OTH exome AF: 0.0372

GnomAD4 genome AF: 0.0574 AC: 8731 AN: 152220 Hom.: 339 Cov.: 32 AF XY: 0.0599 AC XY: 4462 AN XY: 74444

Gnomad4 AFR AF: 0.0976

Gnomad4 AMR AF: 0.0523

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.00231

Gnomad4 SAS AF: 0.0164

Gnomad4 FIN AF: 0.106

Gnomad4 NFE AF: 0.0359

Gnomad4 OTH AF: 0.0469

Alfa AF: 0.0376 Hom.: 126

Bravo AF: 0.0558

TwinsUK AF: 0.0248 AC: 92

ALSPAC AF: 0.0371 AC: 143

ESP6500AA AF: 0.0975 AC: 365

ESP6500EA AF: 0.0282 AC: 232

ExAC AF: 0.0440 AC: 5313

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.0316

EpiControl AF: 0.0314

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Asp1269Glu in exon 43 of COL4A3: This variant is not expected to have clinical significance because it has been identified in 10.45% (691/6614) of Finnish chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs57611801). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 22, 2017	- -

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. -

Autosomal recessive Alport syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Atypical hemolytic-uremic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	9.8
Dann	Benign	0.68
DEOGEN2	Benign	0.063	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.21	N
MutationTaster	Benign	0.70	D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.53	N
REVEL	Benign	0.27
Sift	Benign	0.38	T
Sift4G	Benign	0.96	T
Polyphen		0.022	B
Vest4		0.042
MutPred		0.11		Loss of MoRF binding (P = 0.2243);
MPC		0.18
ClinPred		0.0016	T
GERP RS		0.78
Varity_R		0.046
gMVP		0.11

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: rs57611801; hg19: chr2-228163453;