rs12621551

Variant names:

• chr2-227253687-T-G
• rs12621551
• NM_000091.5:c.765+49T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-227253687-T-G
• chr2-227253687-T-A
• chr2-227253687-T-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.765+49T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.812 in 1,491,480 control chromosomes in the GnomAD database, including 492,651 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (46011 hom., cov: 28)
  • Exomes 𝑓: 0.82 (446640 hom.)
• Consequence: COL4A3 NM_000091.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.81
• Publications: 16 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=-0.86).
• BP6: Variant 2-227253687-T-G is Benign according to our data. Variant chr2-227253687-T-G is described in ClinVar as Benign. ClinVar VariationId is 1172971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.897 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.765+49T>G		intron	N/A	NP_000082.2	Q01955-1
	MFF-DT	NR_102371.1		n.1592+5491A>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.765+49T>G		intron	N/A	ENSP00000379823.3	Q01955-1
	MFF-DT	ENST00000439598.6	TSL:1	n.1592+5491A>C		intron	N/A
	COL4A3	ENST00000871618.1		c.765+49T>G		intron	N/A	ENSP00000541677.1

Frequencies

GnomAD3 genomes AF: 0.776 AC: 117688 AN: 151740 Hom.: 45988 Cov.: 28

Gnomad AFR AF: 0.657

Gnomad AMI AF: 0.947

Gnomad AMR AF: 0.809

Gnomad ASJ AF: 0.834

Gnomad EAS AF: 0.919

Gnomad SAS AF: 0.846

Gnomad FIN AF: 0.804

Gnomad MID AF: 0.829

Gnomad NFE AF: 0.814

Gnomad OTH AF: 0.784

GnomAD2 exomes AF: 0.815 AC: 202388 AN: 248216 AF XY: 0.819

Gnomad AFR exome AF: 0.655

Gnomad AMR exome AF: 0.819

Gnomad ASJ exome AF: 0.833

Gnomad EAS exome AF: 0.915

Gnomad FIN exome AF: 0.806

Gnomad NFE exome AF: 0.815

Gnomad OTH exome AF: 0.822

GnomAD4 exome AF: 0.816 AC: 1092960 AN: 1339622 Hom.: 446640 Cov.: 20 AF XY: 0.817 AC XY: 550538 AN XY: 673450

African (AFR) AF: 0.658 AC: 20350 AN: 30948

American (AMR) AF: 0.817 AC: 36446 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.832 AC: 21141 AN: 25406

East Asian (EAS) AF: 0.929 AC: 36386 AN: 39174

South Asian (SAS) AF: 0.834 AC: 69991 AN: 83884

European-Finnish (FIN) AF: 0.807 AC: 43064 AN: 53330

Middle Eastern (MID) AF: 0.854 AC: 4756 AN: 5566

European-Non Finnish (NFE) AF: 0.814 AC: 814617 AN: 1000300

Other (OTH) AF: 0.819 AC: 46209 AN: 56420

GnomAD4 genome AF: 0.775 AC: 117760 AN: 151858 Hom.: 46011 Cov.: 28 AF XY: 0.777 AC XY: 57659 AN XY: 74206

African (AFR) AF: 0.657 AC: 27174 AN: 41346

American (AMR) AF: 0.810 AC: 12346 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.834 AC: 2894 AN: 3472

East Asian (EAS) AF: 0.919 AC: 4737 AN: 5154

South Asian (SAS) AF: 0.846 AC: 4061 AN: 4800

European-Finnish (FIN) AF: 0.804 AC: 8488 AN: 10556

Middle Eastern (MID) AF: 0.837 AC: 246 AN: 294

European-Non Finnish (NFE) AF: 0.814 AC: 55301 AN: 67968

Other (OTH) AF: 0.783 AC: 1649 AN: 2106

Alfa AF: 0.783 Hom.: 34253

Bravo AF: 0.768

Asia WGS AF: 0.875 AC: 3045 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0080
DANN	Benign	0.37
PhyloP100		-2.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs12621551; hg19: chr2-228118403;