rs56226424

Variant names:

• chr2-227282377-A-G
• rs56226424
• NM_000091.5:c.2501A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000091.5(COL4A3):​c.2501A>G​(p.Lys834Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 1,613,086 control chromosomes in the GnomAD database, including 231 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (12 hom., cov: 31)
  • Exomes 𝑓: 0.016 (219 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.193
• Publications: 8 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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000091.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0045960248).
• BP6: Variant 2-227282377-A-G is Benign according to our data. Variant chr2-227282377-A-G is described in ClinVar as Benign. ClinVar VariationId is 254987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0103 (1563/151726) while in subpopulation NFE AF = 0.0178 (1208/67966). AF 95% confidence interval is 0.0169. There are 12 homozygotes in GnomAd4. There are 694 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR,SD gene

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.2501A>G	p.Lys834Arg	missense	Exon 32 of 52	NP_000082.2	Q01955-1
	MFF-DT	NR_102371.1		n.244-588T>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.2501A>G	p.Lys834Arg	missense	Exon 32 of 52	ENSP00000379823.3	Q01955-1
	MFF-DT	ENST00000439598.6	TSL:1	n.244-588T>C		intron	N/A
	COL4A3	ENST00000871618.1		c.2501A>G	p.Lys834Arg	missense	Exon 32 of 52	ENSP00000541677.1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1564 AN: 151608 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00368

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00354

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0178

Gnomad OTH AF: 0.00720

GnomAD2 exomes AF: 0.0120 AC: 2983 AN: 249468 AF XY: 0.0116

Gnomad AFR exome AF: 0.00194

Gnomad AMR exome AF: 0.00565

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.0194

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0158 AC: 23100 AN: 1461360 Hom.: 219 Cov.: 31 AF XY: 0.0153 AC XY: 11152 AN XY: 727018

African (AFR) AF: 0.00194 AC: 65 AN: 33464

American (AMR) AF: 0.00552 AC: 247 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 288 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.00436 AC: 376 AN: 86256

European-Finnish (FIN) AF: 0.0141 AC: 750 AN: 53370

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5764

European-Non Finnish (NFE) AF: 0.0185 AC: 20601 AN: 1111636

Other (OTH) AF: 0.0124 AC: 748 AN: 60352

GnomAD4 genome AF: 0.0103 AC: 1563 AN: 151726 Hom.: 12 Cov.: 31 AF XY: 0.00936 AC XY: 694 AN XY: 74148

African (AFR) AF: 0.00274 AC: 113 AN: 41278

American (AMR) AF: 0.00368 AC: 56 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00333 AC: 16 AN: 4800

European-Finnish (FIN) AF: 0.0109 AC: 115 AN: 10504

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0178 AC: 1208 AN: 67966

Other (OTH) AF: 0.00713 AC: 15 AN: 2104

Alfa AF: 0.0148 Hom.: 62

Bravo AF: 0.00950

TwinsUK AF: 0.0181 AC: 67

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.00220 AC: 8

ESP6500EA AF: 0.0147 AC: 120

ExAC AF: 0.0124 AC: 1498

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.0161

EpiControl AF: 0.0145

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Alport syndrome (2)
-	-	1	Focal segmental glomerulosclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	5.6
DANN	Benign	0.42
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	-0.050	N
PhyloP100		-0.19
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.13
Sift	Benign	0.35	T
Sift4G	Benign	0.51	T
Polyphen		0.025	B
Vest4		0.040
MPC		0.15
ClinPred		0.00072	T
GERP RS		1.3
Varity_R		0.037
gMVP		0.22
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs56226424; hg19: chr2-228147093; COSMIC: COSV99067739; COSMIC: COSV99067739;