chr2-227237964-C-T

Variant names:

• chr2-227237964-C-T
• rs148393022
• NM_000091.5:c.88-4C>T

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.88-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00441 in 1,608,052 control chromosomes in the GnomAD database, including 328 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (36 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (292 hom.)
• Consequence: COL4A3 NM_000091.5 splice_region, intron
• Scores: Splicing: ADA: 0.0004138
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0460
• 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=-0.55).
• BP6: Variant 2-227237964-C-T is Benign according to our data. Variant chr2-227237964-C-T is described in ClinVar as Benign. ClinVar VariationId is 255008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0563 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.88-4C>T		splice_region intron	N/A	NP_000082.2	Q01955-1
	MFF-DT	NR_102371.1		n.1681+122G>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.88-4C>T		splice_region intron	N/A	ENSP00000379823.3	Q01955-1
	MFF-DT	ENST00000439598.6	TSL:1	n.1681+122G>A		intron	N/A
	COL4A3	ENST00000871618.1		c.88-4C>T		splice_region intron	N/A	ENSP00000541677.1

Frequencies

GnomAD3 genomes AF: 0.00771 AC: 1172 AN: 152072 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0594

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.0200

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00719

GnomAD2 exomes AF: 0.0171 AC: 4275 AN: 249508 AF XY: 0.0131

Gnomad AFR exome AF: 0.00245

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.0226

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.00406 AC: 5912 AN: 1455862 Hom.: 292 Cov.: 27 AF XY: 0.00358 AC XY: 2597 AN XY: 724672

African (AFR) AF: 0.00132 AC: 44 AN: 33366

American (AMR) AF: 0.0999 AC: 4465 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00185 AC: 48 AN: 26016

East Asian (EAS) AF: 0.0233 AC: 925 AN: 39630

South Asian (SAS) AF: 0.000847 AC: 73 AN: 86160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53270

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5752

European-Non Finnish (NFE) AF: 0.000110 AC: 122 AN: 1106806

Other (OTH) AF: 0.00387 AC: 233 AN: 60178

GnomAD4 genome AF: 0.00771 AC: 1174 AN: 152190 Hom.: 36 Cov.: 32 AF XY: 0.00862 AC XY: 641 AN XY: 74398

African (AFR) AF: 0.00255 AC: 106 AN: 41540

American (AMR) AF: 0.0595 AC: 909 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.0199 AC: 103 AN: 5178

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68000

Other (OTH) AF: 0.00712 AC: 15 AN: 2108

Alfa AF: 0.00212 Hom.: 4

Bravo AF: 0.0136

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	8.9
DANN	Benign	0.75
PhyloP100		0.046
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00041
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.010		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: rs148393022; hg19: chr2-228102680;