rs56243460

Variant names:

• chr2-227270755-T-G
• rs56243460
• NM_000091.5:c.1576-15T>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000091.5(COL4A3):​c.1576-15T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0397 in 1,611,610 control chromosomes in the GnomAD database, including 1,779 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (399 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1380 hom.)
• Consequence: COL4A3 NM_000091.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.08
• Publications: 2 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 -16 ACMG points.

• BP6: Variant 2-227270755-T-G is Benign according to our data. Variant chr2-227270755-T-G is described in ClinVar as Benign. ClinVar VariationId is 254984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 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.1576-15T>G		intron	N/A	NP_000082.2	Q01955-1
	MFF-DT	NR_102371.1		n.423-1986A>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A3	ENST00000396578.8	TSL:1 MANE Select	c.1576-15T>G		intron	N/A	ENSP00000379823.3	Q01955-1
	MFF-DT	ENST00000439598.6	TSL:1	n.423-1986A>C		intron	N/A
	COL4A3	ENST00000871618.1		c.1576-15T>G		intron	N/A	ENSP00000541677.1

Frequencies

GnomAD3 genomes AF: 0.0606 AC: 9212 AN: 152128 Hom.: 400 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0534

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0164

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0363

Gnomad OTH AF: 0.0497

GnomAD2 exomes AF: 0.0460 AC: 11456 AN: 249188 AF XY: 0.0424

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.0771

Gnomad ASJ exome AF: 0.0212

Gnomad EAS exome AF: 0.00251

Gnomad FIN exome AF: 0.0986

Gnomad NFE exome AF: 0.0352

Gnomad OTH exome AF: 0.0374

GnomAD4 exome AF: 0.0376 AC: 54827 AN: 1459364 Hom.: 1380 Cov.: 30 AF XY: 0.0365 AC XY: 26541 AN XY: 726230

African (AFR) AF: 0.106 AC: 3535 AN: 33398

American (AMR) AF: 0.0743 AC: 3319 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 503 AN: 26108

East Asian (EAS) AF: 0.00144 AC: 57 AN: 39686

South Asian (SAS) AF: 0.0184 AC: 1589 AN: 86198

European-Finnish (FIN) AF: 0.0927 AC: 4949 AN: 53360

Middle Eastern (MID) AF: 0.0221 AC: 127 AN: 5744

European-Non Finnish (NFE) AF: 0.0347 AC: 38482 AN: 1109868

Other (OTH) AF: 0.0376 AC: 2266 AN: 60310

GnomAD4 genome AF: 0.0605 AC: 9217 AN: 152246 Hom.: 399 Cov.: 32 AF XY: 0.0624 AC XY: 4648 AN XY: 74436

African (AFR) AF: 0.108 AC: 4485 AN: 41528

American (AMR) AF: 0.0535 AC: 818 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 70 AN: 3472

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5180

South Asian (SAS) AF: 0.0162 AC: 78 AN: 4824

European-Finnish (FIN) AF: 0.107 AC: 1134 AN: 10606

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0363 AC: 2471 AN: 68012

Other (OTH) AF: 0.0491 AC: 104 AN: 2116

Alfa AF: 0.0415 Hom.: 60

Bravo AF: 0.0591

Asia WGS AF: 0.0150 AC: 53 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Alport syndrome (1)
-	-	1	Autosomal recessive Alport syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Benign	0.72
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.28		Position offset: 15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs56243460; hg19: chr2-228135471;