rs75519005

Variant names:

• chr2-227283825-C-T
• rs75519005
• NM_000091.5:c.2715C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000091.5(COL4A3):​c.2715C>T​(p.Pro905Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00338 in 1,614,046 control chromosomes in the GnomAD database, including 145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (66 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (79 hom.)
• Consequence: COL4A3 NM_000091.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.234
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 2-227283825-C-T is Benign according to our data. Variant chr2-227283825-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.234 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0621 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.2715C>T	p.Pro905Pro	synonymous	Exon 33 of 52	NP_000082.2	Q01955-1
	MFF-DT	NR_102371.1		n.244-2036G>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.2715C>T	p.Pro905Pro	synonymous	Exon 33 of 52	ENSP00000379823.3	Q01955-1
	MFF-DT	ENST00000439598.6	TSL:1	n.244-2036G>A		intron	N/A
	COL4A3	ENST00000871618.1		c.2715C>T	p.Pro905Pro	synonymous	Exon 33 of 52	ENSP00000541677.1

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2773 AN: 152184 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.0641

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00549

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00443 AC: 1105 AN: 249514 AF XY: 0.00348

Gnomad AFR exome AF: 0.0648

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00313

GnomAD4 exome AF: 0.00183 AC: 2670 AN: 1461744 Hom.: 79 Cov.: 31 AF XY: 0.00152 AC XY: 1107 AN XY: 727186

African (AFR) AF: 0.0674 AC: 2255 AN: 33460

American (AMR) AF: 0.00237 AC: 106 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1111924

Other (OTH) AF: 0.00414 AC: 250 AN: 60388

GnomAD4 genome AF: 0.0183 AC: 2783 AN: 152302 Hom.: 66 Cov.: 32 AF XY: 0.0183 AC XY: 1363 AN XY: 74472

African (AFR) AF: 0.0642 AC: 2665 AN: 41540

American (AMR) AF: 0.00549 AC: 84 AN: 15312

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68036

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.00917 Hom.: 22

Bravo AF: 0.0215

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Alport syndrome (2)
-	-	1	Atypical hemolytic-uremic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.1
DANN	Benign	0.38
PhyloP100		0.23
Mutation Taster		=100/0	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: rs75519005; hg19: chr2-228148541;