rs56226424

chr2-227282377-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000091.5(COL4A3):c.2501A>G(p.Lys834Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 1,613,086 control chromosomes in the GnomAD database, including 231 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (12 hom., cov: 31)
  • Exomes 𝑓: 0.016 (219 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.193

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 -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000091.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0045960248).
• BP6: Variant 2-227282377-A-G is Benign according to our data. Variant chr2-227282377-A-G is described in ClinVar as [Benign]. Clinvar id is 254987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227282377-A-G is described in Lovd as [Likely_benign]. Variant chr2-227282377-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0103 (1563/151726) while in subpopulation NFE AF= 0.0178 (1208/67966). AF 95% confidence interval is 0.0169. There are 12 homozygotes in gnomad4. There are 694 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A3	NM_000091.5	c.2501A>G	p.Lys834Arg	missense_variant	32/52	ENST00000396578.8
MFF-DT	NR_102371.1	n.244-588T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A3	ENST00000396578.8	c.2501A>G	p.Lys834Arg	missense_variant	32/52	1	NM_000091.5	P1
MFF-DT	ENST00000439598.6	n.244-588T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1564 AN: 151608 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00368

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00354

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0178

Gnomad OTH AF: 0.00720

GnomAD3 exomes AF: 0.0120 AC: 2983 AN: 249468 Hom.: 33 AF XY: 0.0116 AC XY: 1572 AN XY: 135348

Gnomad AFR exome AF: 0.00194

Gnomad AMR exome AF: 0.00565

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00415

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.0194

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0158 AC: 23100 AN: 1461360 Hom.: 219 Cov.: 31 AF XY: 0.0153 AC XY: 11152 AN XY: 727018

Gnomad4 AFR exome AF: 0.00194

Gnomad4 AMR exome AF: 0.00552

Gnomad4 ASJ exome AF: 0.0110

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00436

Gnomad4 FIN exome AF: 0.0141

Gnomad4 NFE exome AF: 0.0185

Gnomad4 OTH exome AF: 0.0124

GnomAD4 genome AF: 0.0103 AC: 1563 AN: 151726 Hom.: 12 Cov.: 31 AF XY: 0.00936 AC XY: 694 AN XY: 74148

Gnomad4 AFR AF: 0.00274

Gnomad4 AMR AF: 0.00368

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00333

Gnomad4 FIN AF: 0.0109

Gnomad4 NFE AF: 0.0178

Gnomad4 OTH AF: 0.00713

Alfa AF: 0.0150 Hom.: 33

Bravo AF: 0.00950

TwinsUK AF: 0.0181 AC: 67

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.00220 AC: 8

ESP6500EA AF: 0.0147 AC: 120

ExAC AF: 0.0124 AC: 1498

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.0161

EpiControl AF: 0.0145

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Lys834Arg in exon 32 of COL4A3: This variant is not expected to have clinical significance because it has been identified in 1.88% (1250/66618) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs56226424). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2018	This variant is associated with the following publications: (PMID: 19525337, 14582039, 17216251) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Alport syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 27, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Focal segmental glomerulosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 11, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	5.6
Dann	Benign	0.42
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	-0.050	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.13
Sift	Benign	0.35	T
Sift4G	Benign	0.51	T
Polyphen		0.025	B
Vest4		0.040
MPC		0.15
ClinPred		0.00072	T
GERP RS		1.3
Varity_R		0.037
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs56226424; hg19: chr2-228147093; COSMIC: COSV99067739; COSMIC: COSV99067739;