rs13423714

Variant names:

• chr2-227031936-C-G
• rs13423714
• NM_000092.5:c.3817+9G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-227031936-C-G
• chr2-227031936-C-T
• chr2-227031936-C-A

Variant summary

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

The NM_000092.5(COL4A4):​c.3817+9G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 1,585,900 control chromosomes in the GnomAD database, including 159,225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (16850 hom., cov: 31)
  • Exomes 𝑓: 0.44 (142375 hom.)
• Consequence: COL4A4 NM_000092.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.681
• Publications: 17 publications found

Genes affected

COL4A4 (HGNC:2206): (collagen type IV alpha 4 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. This particular collagen IV subunit, however, is only found in a subset of basement membranes. 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. Mutations in this gene are associated with type II autosomal recessive Alport syndrome (hereditary glomerulonephropathy) and with familial benign hematuria (thin basement membrane disease). Two transcripts, differing only in their transcription start sites, have been identified for this gene and, as is common for collagen genes, multiple polyadenylation sites are found in the 3' UTR. [provided by RefSeq, Jul 2008]

COL4A4 Gene-Disease associations (from GenCC):

• autosomal recessive Alport syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Myriad Women’s Health, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Alport syndrome

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• hematuria, benign familial, 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• autosomal dominant Alport syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-227031936-C-G is Benign according to our data. Variant chr2-227031936-C-G is described in ClinVar as Benign. ClinVar VariationId is 255033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.547 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000092.5. 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
	COL4A4	NM_000092.5	MANE Select	c.3817+9G>C		intron	N/A	NP_000083.3	P53420

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A4	ENST00000396625.5	TSL:5 MANE Select	c.3817+9G>C		intron	N/A	ENSP00000379866.3	P53420

Frequencies

GnomAD3 genomes AF: 0.468 AC: 70961 AN: 151750 Hom.: 16819 Cov.: 31

Gnomad AFR AF: 0.530

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.468

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.388

Gnomad SAS AF: 0.565

Gnomad FIN AF: 0.494

Gnomad MID AF: 0.417

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.436

GnomAD2 exomes AF: 0.473 AC: 116750 AN: 246572 AF XY: 0.472

Gnomad AFR exome AF: 0.537

Gnomad AMR exome AF: 0.533

Gnomad ASJ exome AF: 0.514

Gnomad EAS exome AF: 0.400

Gnomad FIN exome AF: 0.498

Gnomad NFE exome AF: 0.425

Gnomad OTH exome AF: 0.455

GnomAD4 exome AF: 0.442 AC: 633690 AN: 1434032 Hom.: 142375 Cov.: 27 AF XY: 0.444 AC XY: 317537 AN XY: 715148

African (AFR) AF: 0.529 AC: 17407 AN: 32902

American (AMR) AF: 0.528 AC: 23463 AN: 44446

Ashkenazi Jewish (ASJ) AF: 0.522 AC: 13538 AN: 25950

East Asian (EAS) AF: 0.404 AC: 15959 AN: 39546

South Asian (SAS) AF: 0.569 AC: 48691 AN: 85560

European-Finnish (FIN) AF: 0.499 AC: 26607 AN: 53324

Middle Eastern (MID) AF: 0.399 AC: 2240 AN: 5612

European-Non Finnish (NFE) AF: 0.422 AC: 459296 AN: 1087242

Other (OTH) AF: 0.446 AC: 26489 AN: 59450

GnomAD4 genome AF: 0.468 AC: 71036 AN: 151868 Hom.: 16850 Cov.: 31 AF XY: 0.469 AC XY: 34839 AN XY: 74222

African (AFR) AF: 0.531 AC: 21979 AN: 41416

American (AMR) AF: 0.469 AC: 7164 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 1733 AN: 3470

East Asian (EAS) AF: 0.389 AC: 1995 AN: 5134

South Asian (SAS) AF: 0.565 AC: 2708 AN: 4792

European-Finnish (FIN) AF: 0.494 AC: 5218 AN: 10568

Middle Eastern (MID) AF: 0.408 AC: 119 AN: 292

European-Non Finnish (NFE) AF: 0.425 AC: 28844 AN: 67894

Other (OTH) AF: 0.431 AC: 908 AN: 2108

Alfa AF: 0.410 Hom.: 3917

Bravo AF: 0.469

Asia WGS AF: 0.481 AC: 1674 AN: 3478

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	Autosomal recessive Alport syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.45
DANN	Benign	0.58
PhyloP100		-0.68
Mutation Taster		=100/0	polymorphism (auto)

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: rs13423714; hg19: chr2-227896652;