chr2-227008312-A-G

Variant names:

• chr2-227008312-A-G
• rs13419076
• NM_000092.5:c.4523-8T>C

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.4523-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 1,611,954 control chromosomes in the GnomAD database, including 156,585 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 0.48 (18034 hom., cov: 34)
  • Exomes 𝑓: 0.43 (138551 hom.)
• Consequence: COL4A4 NM_000092.5 splice_region, intron
• Scores: Splicing: ADA: 0.000007093
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.81
• Publications: 16 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Orphanet, Ambry Genetics, Myriad Women’s Health
• Alport syndrome

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

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• 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=-0.85).
• BP6: Variant 2-227008312-A-G is Benign according to our data. Variant chr2-227008312-A-G is described in ClinVar as Benign. ClinVar VariationId is 255040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.598 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A4	NM_000092.5	MANE Select	c.4523-8T>C		splice_region intron	N/A	NP_000083.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A4	ENST00000396625.5	TSL:5 MANE Select	c.4523-8T>C		splice_region intron	N/A	ENSP00000379866.3
	COL4A4	ENST00000682098.1		c.190-73T>C		intron	N/A	ENSP00000508331.1

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72851 AN: 152014 Hom.: 17993 Cov.: 34

Gnomad AFR AF: 0.603

Gnomad AMI AF: 0.383

Gnomad AMR AF: 0.467

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.386

Gnomad SAS AF: 0.575

Gnomad FIN AF: 0.477

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.442

GnomAD2 exomes AF: 0.467 AC: 115265 AN: 246872 AF XY: 0.464

Gnomad AFR exome AF: 0.608

Gnomad AMR exome AF: 0.529

Gnomad ASJ exome AF: 0.459

Gnomad EAS exome AF: 0.393

Gnomad FIN exome AF: 0.483

Gnomad NFE exome AF: 0.409

Gnomad OTH exome AF: 0.443

GnomAD4 exome AF: 0.431 AC: 629592 AN: 1459822 Hom.: 138551 Cov.: 46 AF XY: 0.434 AC XY: 314976 AN XY: 726242

African (AFR) AF: 0.602 AC: 20121 AN: 33440

American (AMR) AF: 0.525 AC: 23418 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.464 AC: 12131 AN: 26118

East Asian (EAS) AF: 0.403 AC: 15992 AN: 39686

South Asian (SAS) AF: 0.578 AC: 49823 AN: 86152

European-Finnish (FIN) AF: 0.483 AC: 25772 AN: 53374

Middle Eastern (MID) AF: 0.372 AC: 2143 AN: 5762

European-Non Finnish (NFE) AF: 0.409 AC: 453913 AN: 1110326

Other (OTH) AF: 0.435 AC: 26279 AN: 60346

GnomAD4 genome AF: 0.479 AC: 72941 AN: 152132 Hom.: 18034 Cov.: 34 AF XY: 0.480 AC XY: 35686 AN XY: 74378

African (AFR) AF: 0.604 AC: 25060 AN: 41502

American (AMR) AF: 0.467 AC: 7146 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 1551 AN: 3472

East Asian (EAS) AF: 0.387 AC: 1995 AN: 5156

South Asian (SAS) AF: 0.574 AC: 2774 AN: 4830

European-Finnish (FIN) AF: 0.477 AC: 5055 AN: 10598

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.412 AC: 27980 AN: 67968

Other (OTH) AF: 0.436 AC: 920 AN: 2110

Alfa AF: 0.445 Hom.: 7202

Bravo AF: 0.483

Asia WGS AF: 0.486 AC: 1692 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.85
CADD	Benign	2.7
DANN	Benign	0.34
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000071
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.040		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: rs13419076; hg19: chr2-227873028;