rs80109666

Positions:

• chr2-227254151-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.805G>A​(p.Glu269Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,613,684 control chromosomes in the GnomAD database, including 734 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (164 hom., cov: 32)
  • Exomes 𝑓: 0.010 (570 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.33

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=0.0018270016).
• BP6: Variant 2-227254151-G-A is Benign according to our data. Variant chr2-227254151-G-A is described in ClinVar as [Benign]. Clinvar id is 255006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227254151-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-227254151-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.805G>A	p.Glu269Lys	missense_variant	14/52	ENST00000396578.8	NP_000082.2
MFF-DT	NR_102371.1	n.1592+5027C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.805G>A	p.Glu269Lys	missense_variant	14/52	1	NM_000091.5	ENSP00000379823	P1
MFF-DT	ENST00000439598.6	n.1592+5027C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0293 AC: 4460 AN: 152098 Hom.: 164 Cov.: 32

Gnomad AFR AF: 0.0672

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.0253

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00297

Gnomad OTH AF: 0.0230

GnomAD3 exomes AF: 0.0232 AC: 5790 AN: 249418 Hom.: 284 AF XY: 0.0214 AC XY: 2894 AN XY: 135310

Gnomad AFR exome AF: 0.0694

Gnomad AMR exome AF: 0.00727

Gnomad ASJ exome AF: 0.0142

Gnomad EAS exome AF: 0.153

Gnomad SAS exome AF: 0.0160

Gnomad FIN exome AF: 0.0276

Gnomad NFE exome AF: 0.00337

Gnomad OTH exome AF: 0.0182

GnomAD4 exome AF: 0.00999 AC: 14606 AN: 1461468 Hom.: 570 Cov.: 31 AF XY: 0.00994 AC XY: 7226 AN XY: 727076

Gnomad4 AFR exome AF: 0.0711

Gnomad4 AMR exome AF: 0.00805

Gnomad4 ASJ exome AF: 0.0158

Gnomad4 EAS exome AF: 0.145

Gnomad4 SAS exome AF: 0.0146

Gnomad4 FIN exome AF: 0.0251

Gnomad4 NFE exome AF: 0.00165

Gnomad4 OTH exome AF: 0.0194

GnomAD4 genome AF: 0.0293 AC: 4465 AN: 152216 Hom.: 164 Cov.: 32 AF XY: 0.0306 AC XY: 2276 AN XY: 74440

Gnomad4 AFR AF: 0.0673

Gnomad4 AMR AF: 0.0152

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.143

Gnomad4 SAS AF: 0.0249

Gnomad4 FIN AF: 0.0271

Gnomad4 NFE AF: 0.00296

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.0113 Hom.: 127

Bravo AF: 0.0312

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.0666 AC: 253

ESP6500EA AF: 0.00243 AC: 20

ExAC AF: 0.0234 AC: 2822

Asia WGS AF: 0.0960 AC: 332 AN: 3478

EpiCase AF: 0.00316

EpiControl AF: 0.00373

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Glu269Lys in exon 14 of COL4A3: This variant is not expected to have clinical significance because it has been identified in 15.00% (1291/8608) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs80109666). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 23, 2019	Variant summary: COL4A3 c.805G>A (p.Glu269Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.023 in 249418 control chromosomes, predominantly at a frequency of 0.15 within the East Asian subpopulation in the gnomAD database, including 220 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 73-folds over the estimated maximal expected allele frequency for a pathogenic variant in COL4A3 causing Alport Syndrome, autosomal recessive phenotype (0.002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.805G>A has been reported in the literature in an individual affected with Alport Syndrome, autosomal recessive, however, authors classify the variant as a polymorphism (Zhang_2012). Four ClinVar submissions (evaluation after 2014) cite the variant three times as benign and once as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

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;C5882663:Autosomal dominant Alport syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.019
DANN	Benign	0.70
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.33
Sift	Benign	0.92	T
Sift4G	Benign	0.85	T
Polyphen		0.75	P
Vest4		0.081
MPC		0.24
ClinPred		0.0082	T
GERP RS		-5.1
Varity_R		0.048
gMVP		0.43

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: rs80109666; hg19: chr2-228118867; COSMIC: COSV67414559;