chr2-227267043-G-A

Variant names:

• chr2-227267043-G-A
• rs745472969
• NM_000091.5:c.1459G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM5 PP3_Strong PP5

The NM_000091.5(COL4A3):​c.1459G>A​(p.Gly487Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000929 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G487R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000097 (0 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 5.47
• Publications: 4 publications found

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

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000091.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-227267043-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4072211.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 2-227267043-G-A is Pathogenic according to our data. Variant chr2-227267043-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1309543.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A3	NM_000091.5	c.1459G>A	p.Gly487Ser	missense_variant	Exon 23 of 52	ENST00000396578.8	NP_000082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8	c.1459G>A	p.Gly487Ser	missense_variant	Exon 23 of 52	1	NM_000091.5	ENSP00000379823.3

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000108 AC: 27 AN: 249514 AF XY: 0.0000813

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000971 AC: 142 AN: 1461754 Hom.: 0 Cov.: 31 AF XY: 0.0000853 AC XY: 62 AN XY: 727186

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.000380 AC: 17 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000980 AC: 109 AN: 1111924

Other (OTH) AF: 0.0000994 AC: 6 AN: 60388

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74246

African (AFR) AF: 0.00 AC: 0 AN: 41402

American (AMR) AF: 0.0000655 AC: 1 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000989 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000662 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Aug 02, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A3 gene; Has not been previously published as pathogenic or benign to our knowledge -

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 487 of the COL4A3 protein (p.Gly487Ser). This variant is present in population databases (rs745472969, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with COL4A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1309543). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL4A3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hematuria, benign familial, 2;C5882663:Autosomal dominant Alport syndrome;C5882699:Alport syndrome 3b, autosomal recessive Pathogenic:1

Jun 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant Alport syndrome Uncertain:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.1459G>A(p.Gly487Ser) variant in COL4A3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency of 0.01% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance. However, no details are available for independent assessment. The amino acid Gly at position 487 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly487Ser in COL4A3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.50	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		5.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.66
Sift	Benign	0.038	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.90
MPC		0.75
ClinPred		0.48	T
GERP RS		4.5
Varity_R		0.68
gMVP		0.92
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs745472969; hg19: chr2-228131759; COSMIC: COSV67412847; COSMIC: COSV67412847;