chr2-227108907-A-G

Variant names:

• chr2-227108907-A-G
• rs12475686
• NM_000092.5:c.658-39T>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.658-39T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.623 in 1,597,318 control chromosomes in the GnomAD database, including 311,523 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (28778 hom., cov: 31)
  • Exomes 𝑓: 0.62 (282745 hom.)
• Consequence: COL4A4 NM_000092.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.32
• Publications: 15 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=-0.83).
• BP6: Variant 2-227108907-A-G is Benign according to our data. Variant chr2-227108907-A-G is described in ClinVar as Benign. ClinVar VariationId is 1184738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.63 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.658-39T>C		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.658-39T>C		intron	N/A	ENSP00000379866.3
	COL4A4	ENST00000643379.1		c.658-39T>C		intron	N/A	ENSP00000494516.1
	COL4A4	ENST00000682248.1		n.759-39T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.615 AC: 93423 AN: 151828 Hom.: 28751 Cov.: 31

Gnomad AFR AF: 0.598

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.579

Gnomad ASJ AF: 0.670

Gnomad EAS AF: 0.616

Gnomad SAS AF: 0.564

Gnomad FIN AF: 0.622

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.635

Gnomad OTH AF: 0.630

GnomAD2 exomes AF: 0.604 AC: 143686 AN: 237764 AF XY: 0.607

Gnomad AFR exome AF: 0.595

Gnomad AMR exome AF: 0.504

Gnomad ASJ exome AF: 0.668

Gnomad EAS exome AF: 0.601

Gnomad FIN exome AF: 0.609

Gnomad NFE exome AF: 0.641

Gnomad OTH exome AF: 0.627

GnomAD4 exome AF: 0.624 AC: 901986 AN: 1445372 Hom.: 282745 Cov.: 29 AF XY: 0.623 AC XY: 448147 AN XY: 719214

African (AFR) AF: 0.599 AC: 19840 AN: 33112

American (AMR) AF: 0.512 AC: 22528 AN: 44016

Ashkenazi Jewish (ASJ) AF: 0.672 AC: 17403 AN: 25910

East Asian (EAS) AF: 0.584 AC: 23033 AN: 39426

South Asian (SAS) AF: 0.561 AC: 47811 AN: 85212

European-Finnish (FIN) AF: 0.611 AC: 32408 AN: 53012

Middle Eastern (MID) AF: 0.630 AC: 3623 AN: 5752

European-Non Finnish (NFE) AF: 0.635 AC: 698255 AN: 1099174

Other (OTH) AF: 0.621 AC: 37085 AN: 59758

GnomAD4 genome AF: 0.615 AC: 93501 AN: 151946 Hom.: 28778 Cov.: 31 AF XY: 0.614 AC XY: 45564 AN XY: 74260

African (AFR) AF: 0.598 AC: 24754 AN: 41426

American (AMR) AF: 0.578 AC: 8833 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.670 AC: 2323 AN: 3468

East Asian (EAS) AF: 0.617 AC: 3169 AN: 5140

South Asian (SAS) AF: 0.563 AC: 2707 AN: 4808

European-Finnish (FIN) AF: 0.622 AC: 6564 AN: 10550

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.635 AC: 43189 AN: 67972

Other (OTH) AF: 0.633 AC: 1333 AN: 2106

Alfa AF: 0.631 Hom.: 40511

Bravo AF: 0.609

Asia WGS AF: 0.600 AC: 2084 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 81% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 75. Only high quality variants are reported.

Autosomal recessive Alport syndrome Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.1
DANN	Benign	0.39
PhyloP100		1.3
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: rs12475686; hg19: chr2-227973623; COSMIC: COSV61632915;