rs115324397

Variant names:

• chr2-227245975-C-A
• rs115324397
• NM_000091.5:c.346C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-227245975-C-A
• chr2-227245975-C-T

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.346C>A​(p.Pro116Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00807 in 1,613,656 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P116S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0051 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0084 (74 hom.)
• Consequence: COL4A3 NM_000091.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 2.58
• Publications: 13 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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000091.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.016165346).
• BP6: Variant 2-227245975-C-A is Benign according to our data. Variant chr2-227245975-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254994.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 = 0.00509 (776/152308) while in subpopulation NFE AF = 0.00888 (604/68024). AF 95% confidence interval is 0.00829. There are 6 homozygotes in GnomAd4. There are 342 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.346C>A	p.Pro116Thr	missense	Exon 6 of 52	NP_000082.2	Q01955-1
	MFF-DT	NR_102371.1		n.1593-7801G>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.346C>A	p.Pro116Thr	missense	Exon 6 of 52	ENSP00000379823.3	Q01955-1
	MFF-DT	ENST00000439598.6	TSL:1	n.1593-7801G>T		intron	N/A
	COL4A3	ENST00000871618.1		c.346C>A	p.Pro116Thr	missense	Exon 6 of 52	ENSP00000541677.1

Frequencies

GnomAD3 genomes AF: 0.00511 AC: 778 AN: 152188 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00889

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00485 AC: 1209 AN: 249440 AF XY: 0.00480

Gnomad AFR exome AF: 0.00220

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00394

Gnomad NFE exome AF: 0.00878

Gnomad OTH exome AF: 0.00545

GnomAD4 exome AF: 0.00838 AC: 12246 AN: 1461348 Hom.: 74 Cov.: 30 AF XY: 0.00804 AC XY: 5847 AN XY: 727000

African (AFR) AF: 0.00158 AC: 53 AN: 33462

American (AMR) AF: 0.00177 AC: 79 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000557 AC: 48 AN: 86252

European-Finnish (FIN) AF: 0.00358 AC: 191 AN: 53408

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0103 AC: 11484 AN: 1111552

Other (OTH) AF: 0.00639 AC: 386 AN: 60368

GnomAD4 genome AF: 0.00509 AC: 776 AN: 152308 Hom.: 6 Cov.: 33 AF XY: 0.00459 AC XY: 342 AN XY: 74476

African (AFR) AF: 0.00178 AC: 74 AN: 41572

American (AMR) AF: 0.00393 AC: 60 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00888 AC: 604 AN: 68024

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00706 Hom.: 13

Bravo AF: 0.00546

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00338 AC: 13

ESP6500EA AF: 0.0110 AC: 91

ExAC AF: 0.00500 AC: 604

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00605

EpiControl AF: 0.00741

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	5	not specified (5)
-	-	2	Alport syndrome (2)
-	-	1	Chronic kidney disease (1)
-	-	1	Focal segmental glomerulosclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	0.76	D
MutationAssessor	Benign	1.5	L
PhyloP100		2.6
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.45
MVP		0.91
MPC		0.78
ClinPred		0.013	T
GERP RS		5.2
Varity_R		0.20
gMVP		0.27
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs115324397; hg19: chr2-228110691;