rs56326869

Variant names:

• chr2-227257523-T-C
• rs56326869
• NM_000091.5:c.988-80T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000091.5(COL4A3):​c.988-80T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,165,430 control chromosomes in the GnomAD database, including 533 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (50 hom., cov: 33)
  • Exomes 𝑓: 0.026 (483 hom.)
• Consequence: COL4A3 NM_000091.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.555
• Publications: 5 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=-0.83).
• BP6: Variant 2-227257523-T-C is Benign according to our data. Variant chr2-227257523-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 683248.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 = 0.0194 (2960/152332) while in subpopulation NFE AF = 0.0286 (1947/68022). AF 95% confidence interval is 0.0276. There are 50 homozygotes in GnomAd4. There are 1395 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 AD,AR,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.988-80T>C		intron	N/A	NP_000082.2
	MFF-DT	NR_102371.1		n.1592+1655A>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.988-80T>C		intron	N/A	ENSP00000379823.3
	MFF-DT	ENST00000439598.6	TSL:1	n.1592+1655A>G		intron	N/A
	COL4A3	ENST00000871618.1		c.988-80T>C		intron	N/A	ENSP00000541677.1

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 2961 AN: 152214 Hom.: 50 Cov.: 33

Gnomad AFR AF: 0.00456

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0180

Gnomad ASJ AF: 0.0809

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0199

Gnomad FIN AF: 0.00979

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0286

Gnomad OTH AF: 0.0230

GnomAD4 exome AF: 0.0261 AC: 26469 AN: 1013098 Hom.: 483 AF XY: 0.0266 AC XY: 13938 AN XY: 524324

African (AFR) AF: 0.00519 AC: 128 AN: 24642

American (AMR) AF: 0.0147 AC: 646 AN: 43874

Ashkenazi Jewish (ASJ) AF: 0.0742 AC: 1729 AN: 23296

East Asian (EAS) AF: 0.00 AC: 0 AN: 37448

South Asian (SAS) AF: 0.0218 AC: 1672 AN: 76570

European-Finnish (FIN) AF: 0.00908 AC: 481 AN: 52990

Middle Eastern (MID) AF: 0.0514 AC: 252 AN: 4906

European-Non Finnish (NFE) AF: 0.0287 AC: 20195 AN: 703658

Other (OTH) AF: 0.0299 AC: 1366 AN: 45714

GnomAD4 genome AF: 0.0194 AC: 2960 AN: 152332 Hom.: 50 Cov.: 33 AF XY: 0.0187 AC XY: 1395 AN XY: 74494

African (AFR) AF: 0.00457 AC: 190 AN: 41580

American (AMR) AF: 0.0180 AC: 275 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0809 AC: 281 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.0201 AC: 97 AN: 4828

European-Finnish (FIN) AF: 0.00979 AC: 104 AN: 10622

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0286 AC: 1947 AN: 68022

Other (OTH) AF: 0.0227 AC: 48 AN: 2112

Alfa AF: 0.0223 Hom.: 3

Bravo AF: 0.0196

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.8
DANN	Benign	0.76
PhyloP100		0.56
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: rs56326869; hg19: chr2-228122239;