2-227031936-C-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.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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.681

Publications

17 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=-0.88).

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A4	NM_000092.5 link	c.3817+9G>C		intron_variant	Intron 40 of 47	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5 link	c.3817+9G>C		intron_variant	Intron 40 of 47	5	NM_000092.5	ENSP00000379866.3

Frequencies

GnomAD3 genomes

AF:

0.468

AC:

70961

AN:

151750

Hom.:

16819

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.444

AC XY:

317537

AN XY:

715148

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

18764

37528

56292

75056

93820

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14106

28212

42318

56424

70530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.468

AC:

71036

AN:

151868

Hom.:

16850

Cov.:

AF XY:

0.469

AC XY:

34839

AN XY:

74222

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1939

3877

5816

7754

9693

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

652

1304

1956

2608

3260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.410

Hom.:

3917

Bravo

AF:

0.469

Asia WGS

AF:

0.481

AC:

1674

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

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

- -

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.3817+9G>C in intron 40 of COL4A4: This variant is not expected to have clinica l significance because it is not located within the splice consensus sequence an d has been identified in 57.91% (9317/16088) of South Asian chromosomes by the E xome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs13423 714). -

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 72% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 67. Only high quality variants are reported. -

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

-0.88

CADD

Benign

0.45

(source)

DANN

Benign

0.58

PhyloP100

-0.68

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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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