2-227298737-C-A

Variant names:

• chr2-227298737-C-A
• rs57611801
• NM_000091.5:c.3807C>A

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.3807C>A​(p.Asp1269Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0389 in 1,613,962 control chromosomes in the GnomAD database, including 1,671 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D1269D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.057 (339 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1332 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.256
• Publications: 18 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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 6 uncertain in NM_000091.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0020103753).
• BP6: Variant 2-227298737-C-A is Benign according to our data. Variant chr2-227298737-C-A is described in ClinVar as Benign. ClinVar VariationId is 254995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0951 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.3807C>A	p.Asp1269Glu	missense	Exon 43 of 52	NP_000082.2
	MFF-DT	NR_102371.1		n.243+6723G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	ENST00000396578.8	TSL:1 MANE Select	c.3807C>A	p.Asp1269Glu	missense	Exon 43 of 52	ENSP00000379823.3
	MFF-DT	ENST00000439598.6	TSL:1	n.243+6723G>T		intron	N/A
	COL4A3	ENST00000871618.1		c.3807C>A	p.Asp1269Glu	missense	Exon 43 of 52	ENSP00000541677.1

Frequencies

GnomAD3 genomes AF: 0.0574 AC: 8726 AN: 152102 Hom.: 340 Cov.: 32

Gnomad AFR AF: 0.0978

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0523

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0165

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0359

Gnomad OTH AF: 0.0474

GnomAD2 exomes AF: 0.0449 AC: 11209 AN: 249456 AF XY: 0.0417

Gnomad AFR exome AF: 0.0982

Gnomad AMR exome AF: 0.0760

Gnomad ASJ exome AF: 0.0214

Gnomad EAS exome AF: 0.00250

Gnomad FIN exome AF: 0.0974

Gnomad NFE exome AF: 0.0348

Gnomad OTH exome AF: 0.0363

GnomAD4 exome AF: 0.0370 AC: 54112 AN: 1461742 Hom.: 1332 Cov.: 31 AF XY: 0.0361 AC XY: 26219 AN XY: 727164

African (AFR) AF: 0.0959 AC: 3209 AN: 33474

American (AMR) AF: 0.0732 AC: 3274 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0194 AC: 507 AN: 26132

East Asian (EAS) AF: 0.00141 AC: 56 AN: 39698

South Asian (SAS) AF: 0.0184 AC: 1589 AN: 86250

European-Finnish (FIN) AF: 0.0916 AC: 4891 AN: 53390

Middle Eastern (MID) AF: 0.0221 AC: 127 AN: 5748

European-Non Finnish (NFE) AF: 0.0344 AC: 38211 AN: 1111950

Other (OTH) AF: 0.0372 AC: 2248 AN: 60380

GnomAD4 genome AF: 0.0574 AC: 8731 AN: 152220 Hom.: 339 Cov.: 32 AF XY: 0.0599 AC XY: 4462 AN XY: 74444

African (AFR) AF: 0.0976 AC: 4054 AN: 41518

American (AMR) AF: 0.0523 AC: 801 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 70 AN: 3470

East Asian (EAS) AF: 0.00231 AC: 12 AN: 5184

South Asian (SAS) AF: 0.0164 AC: 79 AN: 4830

European-Finnish (FIN) AF: 0.106 AC: 1126 AN: 10576

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0359 AC: 2445 AN: 68022

Other (OTH) AF: 0.0469 AC: 99 AN: 2112

Alfa AF: 0.0400 Hom.: 385

Bravo AF: 0.0558

TwinsUK AF: 0.0248 AC: 92

ALSPAC AF: 0.0371 AC: 143

ESP6500AA AF: 0.0975 AC: 365

ESP6500EA AF: 0.0282 AC: 232

ExAC AF: 0.0440 AC: 5313

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.0316

EpiControl AF: 0.0314

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	2	Alport syndrome (2)
-	-	1	Atypical hemolytic-uremic syndrome (1)
-	-	1	Autosomal recessive Alport syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	9.8
DANN	Benign	0.68
DEOGEN2	Benign	0.063	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.21	N
PhyloP100		-0.26
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.53	N
REVEL	Benign	0.27
Sift	Benign	0.38	T
Sift4G	Benign	0.96	T
Polyphen		0.022	B
Vest4		0.042
MutPred		0.11		Loss of MoRF binding (P = 0.2243)
MPC		0.18
ClinPred		0.0016	T
GERP RS		0.78
Varity_R		0.046
gMVP		0.11
Mutation Taster		=94/6	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: rs57611801; hg19: chr2-228163453; COSMIC: COSV107359224; COSMIC: COSV107359224;