rs55816283

Variant names:

• chr2-227293305-C-T
• rs55816283
• NM_000091.5:c.3325C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_000091.5(COL4A3):​c.3325C>T​(p.Pro1109Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00601 in 1,613,784 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1109R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0041 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (44 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 1.45
• Publications: 11 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 -11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000091.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0191468).
• BP6: Variant 2-227293305-C-T is Benign according to our data. Variant chr2-227293305-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 254993.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00414 (631/152296) while in subpopulation NFE AF = 0.00609 (414/68028). AF 95% confidence interval is 0.0056. There are 4 homozygotes in GnomAd4. There are 296 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD,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.3325C>T	p.Pro1109Ser	missense	Exon 38 of 52	NP_000082.2	Q01955-1
	MFF-DT	NR_102371.1		n.244-11516G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	ENST00000396578.8	TSL:1 MANE Select	c.3325C>T	p.Pro1109Ser	missense	Exon 38 of 52	ENSP00000379823.3	Q01955-1
	MFF-DT	ENST00000439598.6	TSL:1	n.244-11516G>A		intron	N/A
	COL4A3	ENST00000871618.1		c.3325C>T	p.Pro1109Ser	missense	Exon 38 of 52	ENSP00000541677.1

Frequencies

GnomAD3 genomes AF: 0.00415 AC: 632 AN: 152178 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00610

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00430 AC: 1072 AN: 249366 AF XY: 0.00458

Gnomad AFR exome AF: 0.00116

Gnomad AMR exome AF: 0.00255

Gnomad ASJ exome AF: 0.0108

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00278

Gnomad NFE exome AF: 0.00582

Gnomad OTH exome AF: 0.00429

GnomAD4 exome AF: 0.00621 AC: 9070 AN: 1461488 Hom.: 44 Cov.: 31 AF XY: 0.00613 AC XY: 4460 AN XY: 727056

African (AFR) AF: 0.000956 AC: 32 AN: 33470

American (AMR) AF: 0.00320 AC: 143 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0119 AC: 311 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00375 AC: 323 AN: 86234

European-Finnish (FIN) AF: 0.00262 AC: 140 AN: 53408

Middle Eastern (MID) AF: 0.00398 AC: 22 AN: 5522

European-Non Finnish (NFE) AF: 0.00699 AC: 7775 AN: 1111958

Other (OTH) AF: 0.00537 AC: 324 AN: 60364

GnomAD4 genome AF: 0.00414 AC: 631 AN: 152296 Hom.: 4 Cov.: 32 AF XY: 0.00398 AC XY: 296 AN XY: 74462

African (AFR) AF: 0.00137 AC: 57 AN: 41562

American (AMR) AF: 0.00281 AC: 43 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00498 AC: 24 AN: 4824

European-Finnish (FIN) AF: 0.00320 AC: 34 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00609 AC: 414 AN: 68028

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00584 Hom.: 5

Bravo AF: 0.00419

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00108 AC: 4

ESP6500EA AF: 0.00735 AC: 60

ExAC AF: 0.00423 AC: 511

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00567

EpiControl AF: 0.00699

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	1	-	Alport syndrome (1)
-	-	1	COL4A3-related disorder (1)
-	-	1	Kidney disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.019	T
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.5	L
PhyloP100		1.5
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.52
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.13	T
Polyphen		0.75	P
Vest4		0.50
MVP		0.87
MPC		0.19
ClinPred		0.012	T
GERP RS		4.8
Varity_R		0.14
gMVP		0.36
Mutation Taster		=91/9	polymorphism

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: rs55816283; hg19: chr2-228158021; COSMIC: COSV107359216;