rs55667591

Variant names:

• chr2-227251131-A-C
• rs55667591
• NM_000091.5:c.547-9A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000091.5(COL4A3):​c.547-9A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0221 in 1,606,522 control chromosomes in the GnomAD database, including 1,427 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (174 hom., cov: 32)
  • Exomes 𝑓: 0.022 (1253 hom.)
• Consequence: COL4A3 NM_000091.5 intron
• Scores: Splicing: ADA: 0.00004422
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0470
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 2-227251131-A-C is Benign according to our data. Variant chr2-227251131-A-C is described in ClinVar as Benign. ClinVar VariationId is 255003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0911 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.547-9A>C		intron	N/A	NP_000082.2	Q01955-1
	MFF-DT	NR_102371.1		n.1592+8047T>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	ENST00000396578.8	TSL:1 MANE Select	c.547-9A>C		intron	N/A	ENSP00000379823.3	Q01955-1
	MFF-DT	ENST00000439598.6	TSL:1	n.1592+8047T>G		intron	N/A
	COL4A3	ENST00000871618.1		c.547-9A>C		intron	N/A	ENSP00000541677.1

Frequencies

GnomAD3 genomes AF: 0.0264 AC: 4012 AN: 152178 Hom.: 170 Cov.: 32

Gnomad AFR AF: 0.00415

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0945

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0998

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0178

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.0431 AC: 10748 AN: 249262 AF XY: 0.0375

Gnomad AFR exome AF: 0.00310

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.00626

Gnomad EAS exome AF: 0.000278

Gnomad FIN exome AF: 0.0893

Gnomad NFE exome AF: 0.0170

Gnomad OTH exome AF: 0.0293

GnomAD4 exome AF: 0.0217 AC: 31506 AN: 1454226 Hom.: 1253 Cov.: 30 AF XY: 0.0208 AC XY: 15034 AN XY: 724092

African (AFR) AF: 0.00297 AC: 99 AN: 33304

American (AMR) AF: 0.173 AC: 7719 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00583 AC: 152 AN: 26084

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39668

South Asian (SAS) AF: 0.0118 AC: 1020 AN: 86082

European-Finnish (FIN) AF: 0.0833 AC: 4447 AN: 53382

Middle Eastern (MID) AF: 0.00769 AC: 44 AN: 5722

European-Non Finnish (NFE) AF: 0.0153 AC: 16945 AN: 1105194

Other (OTH) AF: 0.0179 AC: 1074 AN: 60100

GnomAD4 genome AF: 0.0264 AC: 4024 AN: 152296 Hom.: 174 Cov.: 32 AF XY: 0.0309 AC XY: 2298 AN XY: 74464

African (AFR) AF: 0.00414 AC: 172 AN: 41582

American (AMR) AF: 0.0952 AC: 1456 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0118 AC: 57 AN: 4828

European-Finnish (FIN) AF: 0.0998 AC: 1058 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0178 AC: 1213 AN: 68020

Other (OTH) AF: 0.0203 AC: 43 AN: 2114

Alfa AF: 0.0169 Hom.: 22

Bravo AF: 0.0264

Asia WGS AF: 0.00780 AC: 27 AN: 3476

EpiCase AF: 0.0133

EpiControl AF: 0.0146

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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	-0.68
CADD	Benign	13
DANN	Benign	0.84
PhyloP100		0.047
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000044
dbscSNV1_RF	Benign	0.18
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: rs55667591; hg19: chr2-228115847; COSMIC: COSV67414050;