rs73996414

chr2-227304032-C-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000091.5(COL4A3):c.4041C>A(p.Asp1347Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00459 in 1,614,098 control chromosomes in the GnomAD database, including 256 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 0.024 (146 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (110 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.27

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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000091.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0026836097).
• BP6: Variant 2-227304032-C-A is Benign according to our data. Variant chr2-227304032-C-A is described in ClinVar as [Benign]. Clinvar id is 334780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227304032-C-A is described in Lovd as [Likely_benign]. Variant chr2-227304032-C-A is described in Lovd as [Likely_pathogenic].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A3	NM_000091.5	c.4041C>A	p.Asp1347Glu	missense_variant	46/52	ENST00000396578.8
MFF-DT	NR_102371.1	n.243+1428G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A3	ENST00000396578.8	c.4041C>A	p.Asp1347Glu	missense_variant	46/52	1	NM_000091.5	P1
MFF-DT	ENST00000439598.6	n.243+1428G>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0235 AC: 3579 AN: 152162 Hom.: 146 Cov.: 32

Gnomad AFR AF: 0.0817

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00746

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.00640 AC: 1596 AN: 249314 Hom.: 51 AF XY: 0.00489 AC XY: 661 AN XY: 135278

Gnomad AFR exome AF: 0.0837

Gnomad AMR exome AF: 0.00418

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00234

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000460

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.00262 AC: 3831 AN: 1461818 Hom.: 110 Cov.: 31 AF XY: 0.00230 AC XY: 1676 AN XY: 727210

Gnomad4 AFR exome AF: 0.0814

Gnomad4 AMR exome AF: 0.00459

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.00123

Gnomad4 SAS exome AF: 0.00128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000313

Gnomad4 OTH exome AF: 0.00540

GnomAD4 genome AF: 0.0235 AC: 3584 AN: 152280 Hom.: 146 Cov.: 32 AF XY: 0.0225 AC XY: 1678 AN XY: 74460

Gnomad4 AFR AF: 0.0816

Gnomad4 AMR AF: 0.00745

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00231

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00526 Hom.: 46

Bravo AF: 0.0276

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0827 AC: 330

ESP6500EA AF: 0.000240 AC: 2

ExAC AF: 0.00776 AC: 938

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely 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	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Asp1347Glu in exon 46 of COL4A3: This variant is not expected to have clinical significance because it has been identified in 8.37% (820/9794) of African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs73996414). -

Autosomal dominant Alport syndrome;C4746745:Autosomal recessive Alport syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 01, 2017

- -

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. -

Atypical hemolytic-uremic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 07, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	6.1
Dann	Benign	0.89
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	-0.16	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.21
Sift	Benign	0.35	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.086
MutPred		0.23		Loss of catalytic residue at G1349 (P = 0.1665);
MVP		0.55
MPC		0.18
ClinPred		0.0031	T
GERP RS		-2.0
Varity_R		0.061
gMVP		0.047

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: rs73996414; hg19: chr2-228168748;