2-227266453-A-G

Variant names:

• chr2-227266453-A-G
• rs11677877
• NM_000091.5:c.1352A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000091.5(COL4A3):​c.1352A>G​(p.His451Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0802 in 1,613,644 control chromosomes in the GnomAD database, including 5,881 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 Likely 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. H451P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.083 (627 hom., cov: 32)
  • Exomes 𝑓: 0.080 (5254 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.0730
• Publications: 40 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 -18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000091.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0055891275).
• BP6: Variant 2-227266453-A-G is Benign according to our data. Variant chr2-227266453-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.163 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.1352A>G	p.His451Arg	missense	Exon 22 of 52	NP_000082.2	Q01955-1
	MFF-DT	NR_102371.1		n.656-518T>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.1352A>G	p.His451Arg	missense	Exon 22 of 52	ENSP00000379823.3	Q01955-1
	MFF-DT	ENST00000439598.6	TSL:1	n.656-518T>C		intron	N/A
	COL4A3	ENST00000871618.1		c.1352A>G	p.His451Arg	missense	Exon 22 of 52	ENSP00000541677.1

Frequencies

GnomAD3 genomes AF: 0.0831 AC: 12636 AN: 152130 Hom.: 620 Cov.: 32

Gnomad AFR AF: 0.0685

Gnomad AMI AF: 0.0582

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0311

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0732

Gnomad OTH AF: 0.0936

GnomAD2 exomes AF: 0.0969 AC: 24153 AN: 249370 AF XY: 0.0958

Gnomad AFR exome AF: 0.0693

Gnomad AMR exome AF: 0.178

Gnomad ASJ exome AF: 0.0900

Gnomad EAS exome AF: 0.153

Gnomad FIN exome AF: 0.0310

Gnomad NFE exome AF: 0.0761

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.0799 AC: 116781 AN: 1461396 Hom.: 5254 Cov.: 31 AF XY: 0.0807 AC XY: 58703 AN XY: 727044

African (AFR) AF: 0.0671 AC: 2248 AN: 33478

American (AMR) AF: 0.177 AC: 7905 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0902 AC: 2356 AN: 26128

East Asian (EAS) AF: 0.123 AC: 4862 AN: 39682

South Asian (SAS) AF: 0.112 AC: 9649 AN: 86246

European-Finnish (FIN) AF: 0.0357 AC: 1909 AN: 53404

Middle Eastern (MID) AF: 0.101 AC: 581 AN: 5768

European-Non Finnish (NFE) AF: 0.0735 AC: 81700 AN: 1111612

Other (OTH) AF: 0.0923 AC: 5571 AN: 60374

GnomAD4 genome AF: 0.0832 AC: 12664 AN: 152248 Hom.: 627 Cov.: 32 AF XY: 0.0837 AC XY: 6229 AN XY: 74444

African (AFR) AF: 0.0685 AC: 2846 AN: 41538

American (AMR) AF: 0.168 AC: 2570 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 347 AN: 3466

East Asian (EAS) AF: 0.152 AC: 788 AN: 5188

South Asian (SAS) AF: 0.106 AC: 512 AN: 4828

European-Finnish (FIN) AF: 0.0311 AC: 330 AN: 10616

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0731 AC: 4975 AN: 68014

Other (OTH) AF: 0.100 AC: 212 AN: 2116

Alfa AF: 0.0828 Hom.: 2760

Bravo AF: 0.0931

TwinsUK AF: 0.0769 AC: 285

ALSPAC AF: 0.0719 AC: 277

ESP6500AA AF: 0.0665 AC: 245

ESP6500EA AF: 0.0767 AC: 628

ExAC AF: 0.0938 AC: 11330

Asia WGS AF: 0.140 AC: 487 AN: 3478

EpiCase AF: 0.0875

EpiControl AF: 0.0899

ClinVar

ClinVar submissions

Significance: Benign/Likely 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 recessive Alport syndrome (1)
-	-	1	Focal segmental glomerulosclerosis (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	-0.41
CADD	Benign	0.048
DANN	Benign	0.49
DEOGEN2	Benign	0.39	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.063	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	-0.21	N
PhyloP100		-0.073
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.21
Sift	Benign	0.62	T
Sift4G	Benign	0.59	T
Polyphen		0.14	B
Vest4		0.0090
MPC		0.25
ClinPred		0.00055	T
GERP RS		-4.1
Varity_R		0.041
gMVP		0.12
Mutation Taster		=100/0	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: rs11677877; hg19: chr2-228131169; COSMIC: COSV67414527; COSMIC: COSV67414527;