2-227248459-A-G

Variant names:

• chr2-227248459-A-G
• rs6436669
• NM_000091.5:c.485A>G

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.485A>G​(p.Glu162Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.833 in 1,609,424 control chromosomes in the GnomAD database, including 560,380 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E162E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.78 (46870 hom., cov: 30)
  • Exomes 𝑓: 0.84 (513510 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.228
• Publications: 53 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=1.2934814E-6).
• BP6: Variant 2-227248459-A-G is Benign according to our data. Variant chr2-227248459-A-G is described in ClinVar as Benign. ClinVar VariationId is 255001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.885 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.485A>G	p.Glu162Gly	missense	Exon 9 of 52	NP_000082.2	Q01955-1
	MFF-DT	NR_102371.1		n.1593-10285T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	ENST00000396578.8	TSL:1 MANE Select	c.485A>G	p.Glu162Gly	missense	Exon 9 of 52	ENSP00000379823.3	Q01955-1
	MFF-DT	ENST00000439598.6	TSL:1	n.1593-10285T>C		intron	N/A
	COL4A3	ENST00000871618.1		c.485A>G	p.Glu162Gly	missense	Exon 9 of 52	ENSP00000541677.1

Frequencies

GnomAD3 genomes AF: 0.780 AC: 118480 AN: 151958 Hom.: 46841 Cov.: 30

Gnomad AFR AF: 0.626

Gnomad AMI AF: 0.790

Gnomad AMR AF: 0.847

Gnomad ASJ AF: 0.778

Gnomad EAS AF: 0.907

Gnomad SAS AF: 0.860

Gnomad FIN AF: 0.819

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.837

Gnomad OTH AF: 0.776

GnomAD2 exomes AF: 0.835 AC: 208114 AN: 249350 AF XY: 0.837

Gnomad AFR exome AF: 0.628

Gnomad AMR exome AF: 0.887

Gnomad ASJ exome AF: 0.775

Gnomad EAS exome AF: 0.919

Gnomad FIN exome AF: 0.825

Gnomad NFE exome AF: 0.835

Gnomad OTH exome AF: 0.822

GnomAD4 exome AF: 0.838 AC: 1221628 AN: 1457348 Hom.: 513510 Cov.: 33 AF XY: 0.838 AC XY: 607873 AN XY: 725274

African (AFR) AF: 0.622 AC: 20765 AN: 33360

American (AMR) AF: 0.881 AC: 39370 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.775 AC: 20199 AN: 26080

East Asian (EAS) AF: 0.890 AC: 35295 AN: 39664

South Asian (SAS) AF: 0.857 AC: 73891 AN: 86178

European-Finnish (FIN) AF: 0.826 AC: 44034 AN: 53334

Middle Eastern (MID) AF: 0.712 AC: 4101 AN: 5758

European-Non Finnish (NFE) AF: 0.843 AC: 934240 AN: 1108060

Other (OTH) AF: 0.826 AC: 49733 AN: 60208

GnomAD4 genome AF: 0.780 AC: 118560 AN: 152076 Hom.: 46870 Cov.: 30 AF XY: 0.781 AC XY: 58037 AN XY: 74358

African (AFR) AF: 0.626 AC: 25941 AN: 41426

American (AMR) AF: 0.847 AC: 12954 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.778 AC: 2699 AN: 3470

East Asian (EAS) AF: 0.907 AC: 4696 AN: 5178

South Asian (SAS) AF: 0.861 AC: 4150 AN: 4820

European-Finnish (FIN) AF: 0.819 AC: 8670 AN: 10584

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.837 AC: 56907 AN: 67990

Other (OTH) AF: 0.775 AC: 1640 AN: 2116

Alfa AF: 0.820 Hom.: 171232

Bravo AF: 0.775

TwinsUK AF: 0.829 AC: 3075

ALSPAC AF: 0.846 AC: 3260

ESP6500AA AF: 0.640 AC: 2326

ESP6500EA AF: 0.828 AC: 6760

ExAC AF: 0.830 AC: 100265

Asia WGS AF: 0.848 AC: 2948 AN: 3478

EpiCase AF: 0.823

EpiControl AF: 0.829

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	0.052
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	13
DANN	Benign	0.54
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.23
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.16
Sift	Benign	0.83	T
Sift4G	Benign	0.42	T
Polyphen		0.019	B
Vest4		0.065
MPC		0.23
ClinPred		0.0032	T
GERP RS		1.2
Varity_R		0.033
gMVP		0.46
Mutation Taster		=98/2	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: rs6436669; hg19: chr2-228113175; COSMIC: COSV107512073;