2-227238007-G-C

Variant names:

• chr2-227238007-G-C
• rs13424243
• NM_000091.5:c.127G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000091.5(COL4A3):​c.127G>C​(p.Gly43Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 1,604,472 control chromosomes in the GnomAD database, including 97,778 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G43W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.32 (8201 hom., cov: 31)
  • Exomes 𝑓: 0.34 (89577 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.14
• Publications: 39 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005469084).
• BP6: Variant 2-227238007-G-C is Benign according to our data. Variant chr2-227238007-G-C is described in ClinVar as Benign. ClinVar VariationId is 254978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000091.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	NM_000091.5	MANE Select	c.127G>C	p.Gly43Arg	missense	Exon 2 of 52	NP_000082.2	Q01955-1
	MFF-DT	NR_102371.1		n.1681+79C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	ENST00000396578.8	TSL:1 MANE Select	c.127G>C	p.Gly43Arg	missense	Exon 2 of 52	ENSP00000379823.3	Q01955-1
	MFF-DT	ENST00000439598.6	TSL:1	n.1681+79C>G		intron	N/A
	COL4A3	ENST00000871618.1		c.127G>C	p.Gly43Arg	missense	Exon 2 of 52	ENSP00000541677.1

Frequencies

GnomAD3 genomes AF: 0.319 AC: 48484 AN: 151848 Hom.: 8194 Cov.: 31

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.0488

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.274

Gnomad NFE AF: 0.359

Gnomad OTH AF: 0.323

GnomAD2 exomes AF: 0.284 AC: 70806 AN: 249520 AF XY: 0.282

Gnomad AFR exome AF: 0.308

Gnomad AMR exome AF: 0.218

Gnomad ASJ exome AF: 0.337

Gnomad EAS exome AF: 0.0388

Gnomad FIN exome AF: 0.334

Gnomad NFE exome AF: 0.362

Gnomad OTH exome AF: 0.314

GnomAD4 exome AF: 0.341 AC: 494969 AN: 1452506 Hom.: 89577 Cov.: 28 AF XY: 0.334 AC XY: 241510 AN XY: 723070

African (AFR) AF: 0.311 AC: 10361 AN: 33306

American (AMR) AF: 0.226 AC: 10095 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 8976 AN: 26036

East Asian (EAS) AF: 0.0735 AC: 2911 AN: 39610

South Asian (SAS) AF: 0.144 AC: 12396 AN: 86116

European-Finnish (FIN) AF: 0.331 AC: 17611 AN: 53252

Middle Eastern (MID) AF: 0.280 AC: 1610 AN: 5744

European-Non Finnish (NFE) AF: 0.373 AC: 411686 AN: 1103730

Other (OTH) AF: 0.322 AC: 19323 AN: 60042

GnomAD4 genome AF: 0.319 AC: 48521 AN: 151966 Hom.: 8201 Cov.: 31 AF XY: 0.309 AC XY: 22974 AN XY: 74262

African (AFR) AF: 0.313 AC: 12972 AN: 41422

American (AMR) AF: 0.273 AC: 4169 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 1212 AN: 3470

East Asian (EAS) AF: 0.0487 AC: 252 AN: 5170

South Asian (SAS) AF: 0.140 AC: 674 AN: 4806

European-Finnish (FIN) AF: 0.339 AC: 3577 AN: 10552

Middle Eastern (MID) AF: 0.284 AC: 83 AN: 292

European-Non Finnish (NFE) AF: 0.359 AC: 24409 AN: 67980

Other (OTH) AF: 0.319 AC: 672 AN: 2108

Alfa AF: 0.322 Hom.: 5112

Bravo AF: 0.318

TwinsUK AF: 0.396 AC: 1469

ALSPAC AF: 0.378 AC: 1457

ESP6500AA AF: 0.306 AC: 1134

ESP6500EA AF: 0.371 AC: 3032

ExAC AF: 0.288 AC: 34832

Asia WGS AF: 0.123 AC: 427 AN: 3478

EpiCase AF: 0.357

EpiControl AF: 0.363

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	not provided (3)
-	-	2	Alport syndrome (2)
-	-	1	Autosomal dominant Alport syndrome (1)
-	-	1	Autosomal recessive Alport syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.23
Eigen_PC	Benign	-0.025
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.8	T
MutationAssessor	Pathogenic	4.1	H
PhyloP100		1.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.10
MutPred		0.86		Gain of sheet (P = 0.0344)
MPC		0.82
ClinPred		0.048	T
GERP RS		4.3
Varity_R		0.61
gMVP		0.61
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13424243; hg19: chr2-228102723; COSMIC: COSV67415437; COSMIC: COSV67415437;