2-227008312-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Variant links:

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

COL4A4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A4	NM_000092.5 link	c.4523-8T>C		splice_region_variant, intron_variant	Intron 46 of 47	ENST00000396625.5	NP_000083.3	P53420

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5 link	c.4523-8T>C		splice_region_variant, intron_variant	Intron 46 of 47	5	NM_000092.5	ENSP00000379866.3		P53420
COL4A4	ENST00000682098.1 link	c.190-73T>C		intron_variant	Intron 1 of 2			ENSP00000508331.1		A0A804HLF6

Frequencies

GnomAD3 genomes

AF:

0.479

AC:

72851

AN:

152014

Hom.:

17993

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.434

AC XY:

314976

AN XY:

726242

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

19192

38384

57576

76768

95960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.479

AC:

72941

AN:

152132

Hom.:

18034

Cov.:

AF XY:

0.480

AC XY:

35686

AN XY:

74378

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1960

3919

5879

7838

9798

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.445

Hom.:

7202

Bravo

AF:

0.483

Asia WGS

AF:

0.486

AC:

1692

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.4523-8T>C in intron 46 of COL4A4: This variant is not expected to have clinica l significance because a T>C change at this position does not diverge from the s plice consensus sequence and is therefore unlikely to impact splicing. It has be en identified in 64.07% (847/1322) of African chromosomes by the 1000 Genomes Pr oject (Phase 3; dbSNP rs13419076). -

May 09, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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 70% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 65. Only high quality variants are reported. -

Nov 29, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 03, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Alport syndrome

Benign:2

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

2.7

(source)

DANN

Benign

0.34

PhyloP100

-1.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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2-227008312-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over