2-227240220-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000091.5(COL4A3):​c.222G>T​(p.Pro74Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,609,860 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0014 ( 9 hom. )

Consequence

COL4A3
NM_000091.5 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -1.53
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 2-227240220-G-T is Benign according to our data. Variant chr2-227240220-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 254986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227240220-G-T is described in Lovd as [Likely_benign]. Variant chr2-227240220-G-T is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-1.53 with no splicing effect.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00144 (2098/1457672) while in subpopulation MID AF= 0.0141 (81/5762). AF 95% confidence interval is 0.0116. There are 9 homozygotes in gnomad4_exome. There are 1060 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 9 SD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL4A3NM_000091.5 linkuse as main transcriptc.222G>T p.Pro74Pro synonymous_variant 3/52 ENST00000396578.8 NP_000082.2 Q01955-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL4A3ENST00000396578.8 linkuse as main transcriptc.222G>T p.Pro74Pro synonymous_variant 3/521 NM_000091.5 ENSP00000379823.3 Q01955-1

Frequencies

GnomAD3 genomes
AF:
0.00125
AC:
190
AN:
152070
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000435
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00144
Gnomad ASJ
AF:
0.0121
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000830
Gnomad FIN
AF:
0.000189
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.00137
Gnomad OTH
AF:
0.00335
GnomAD3 exomes
AF:
0.00168
AC:
404
AN:
240766
Hom.:
3
AF XY:
0.00162
AC XY:
212
AN XY:
130488
show subpopulations
Gnomad AFR exome
AF:
0.000273
Gnomad AMR exome
AF:
0.00249
Gnomad ASJ exome
AF:
0.0106
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000998
Gnomad FIN exome
AF:
0.000194
Gnomad NFE exome
AF:
0.00145
Gnomad OTH exome
AF:
0.00341
GnomAD4 exome
AF:
0.00144
AC:
2098
AN:
1457672
Hom.:
9
Cov.:
32
AF XY:
0.00146
AC XY:
1060
AN XY:
724576
show subpopulations
Gnomad4 AFR exome
AF:
0.00114
Gnomad4 AMR exome
AF:
0.00257
Gnomad4 ASJ exome
AF:
0.0118
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.000882
Gnomad4 FIN exome
AF:
0.000226
Gnomad4 NFE exome
AF:
0.00118
Gnomad4 OTH exome
AF:
0.00266
GnomAD4 genome
AF:
0.00125
AC:
190
AN:
152188
Hom.:
0
Cov.:
32
AF XY:
0.00113
AC XY:
84
AN XY:
74422
show subpopulations
Gnomad4 AFR
AF:
0.000434
Gnomad4 AMR
AF:
0.00144
Gnomad4 ASJ
AF:
0.0121
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000831
Gnomad4 FIN
AF:
0.000189
Gnomad4 NFE
AF:
0.00137
Gnomad4 OTH
AF:
0.00332
Alfa
AF:
0.00172
Hom.:
1
Bravo
AF:
0.00159

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:7
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsNov 14, 2018- -
Benign, criteria provided, single submitterclinical testingGeneDxJul 03, 2019This variant is associated with the following publications: (PMID: 17216251, 14582039) -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenDec 01, 2022COL4A3: BP4, BP7 -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Alport syndrome Benign:2
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, no assertion criteria providedclinical testingNatera, Inc.Dec 03, 2019- -
not specified Benign:1
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
COL4A3-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMay 20, 2021This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.82
CADD
Benign
0.24
DANN
Benign
0.64

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs187950806; hg19: chr2-228104936; API